Pyrazole ether derivatives as anti-inflammatory/analgesic agents

ABSTRACT

The present invention relates to compounds of the formula  
                 
 
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , A, X and Y are defined as in the specification, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the invention are useful in the treatment or alleviation of inflammation and other inflammation associated disorders, such as arthritis, colon cancer, and Alzheimer&#39;s disease in mammals, preferably humans, dogs, cats and livestock animals.

BACKGROUND OF THE INVENTION

[0001] This invention relates to pyrazole ethers, thioethers and aminederivatives, methods of treatment and pharmaceutical compositions forthe treatment of cyclooxygenase mediated diseases. The compounds of thisinvention inhibit the biosynthesis of prostaglandins by intervention ofthe action of the enzyme cyclooxygenase on arachidonic acid, and aretherefore useful in the treatment or alleviation of inflammation, otherinflammation associated disorders, such as arthritis, neurodegenerationand colon cancer, in mammals, preferably humans; dogs, cats or livestockanimals.

[0002] Nonsteroidal anti-inflammatory drugs (NSAID's) are widely used intreating pain and the signs and symptoms of arthritis because of theiranalgesic and anti-inflammatory activity. It is accepted that commonNSAID's work by blocking the activity of cyclooxygenase (COX), alsoknown as prostaglandin G/H synthase (PGHS), the enzyme that convertsarachidonic acid into prostanoids. Prostaglandins, especiallyprostaglandin E₂ (PGE₂), which is the predominant eicosanoid detected ininflammation conditions, are mediators of pain, fever and other symptomsassociated with inflammation. Inhibition of the biosynthesis ofprostaglandins has been a therapeutic target of anti-inflammatory drugdiscovery. The therapeutic use of conventional NSAID's is, however,limited due to drug associated side effects, including life threateningulceration and renal toxicity. An alternative to NSAID's is the use ofcorticosteroids; however, long term therapy can also result in severeside effects.

[0003] The use of NSAID's in dogs and cats has been more limited thanthat in humans, e.g., only three such NSAID's have been approved by theFood and Drug Administration, Committee on Veterinary Medicine(FDA/CVM), for use in dogs in the United States, i.e., ETOGESIC®(etodolac), AROUEL® (meclofenamic acid) and RIMADYL® (carprofen).Consequently, there is less experience and knowledge in veterinarymedicine about safety and efficacy issues surrounding the use of NSAID'sin dogs. In veterinary medicine, for example, the most common indicationfor NSAID's is the treatment of degenerative joint disease (DJD), whichin dogs often results from a variety of developmental diseases, e.g.,hip dysplasia and osteochondrosis, as well as from traumatic injuries tojoints. In addition to the treatment of chronic pain and inflammation,NSAID's are also useful in dogs for treating post-surgical acute pain,as well as for treating clinical signs associated with osteoarthritis.

[0004] Two forms of COX are now known, a constitutive isoform (COX-1)and an inducible isoform (COX-2) of which expression is upregulated atsites of inflammation (Vane, J. R.; Mitchell, J. A.; Appleton, I.;Tomlinson, A.; Bishop-Bailey, D.; Croxtoll, J.; Willoughby, D. A. Proc.Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 is thought to play aphysiological role and to be responsible for gastrointestinal and renalprotection. On the other hand, COX-2 appears to play a pathological roleand is believed to be the predominant isoform present in inflammationconditions. A pathological role for prostaglandins has been implicatedin a number of human disease states including rheumatoid arthritis andosteoarthritis, pyrexia, asthma, bone resorption, cardiovasculardiseases, dysmenorrhea, premature labor, nephritis, nephrosis,atherosclerosis, hypotension, shock, pain, cancer, and Alzheimerdisease. It is believed that compounds that selectively inhibit thebiosynthesis of prostaglandins by intervention of the induction phase ofthe inducible enzyme COX-2 and/or by intervention of the activity of theenzyme COX-2 on arachidonic acid would provide alternate therapy to theuse of NSAID's or corticosteroids in that such compounds would exertanti-inflammatory effects without the adverse side effects associatedwith COX-1 inhibition.

[0005] A variety of sulfonylbenzene compounds which inhibit COX havebeen disclosed in patent publications WO 97/16435, WO 97/14691, WO96/19469, WO 96/36623, WO 96/03392, WO 96/03387, WO 97/727181, WO96/936617, WO 96/19469, WO 96/08482, WO 95/00501, WO 95/15315, WO95/15316, WO 95/15317, WO 95/15318, WO 97/13755, EP 0799523, EP 418845,EP 554829, WO 99/15513, WO 99/23087 and WO 97/11704.

SUMMARY OF THE INVENTION

[0006] The present invention relates to compounds of the formula

[0007] wherein

[0008] A is a, S, SO, SO₂ or NR⁴,

[0009] X is CR⁷ or N;

[0010] Y is CR⁸ or N;

[0011] R¹ is (C₁-C₆)alkyl or —NH₂;

[0012] R² is hydrogen, halo (more preferably chloro or fluoro, mostpreferably fluoro), hydroxy, mercapto, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy optionally substituted with one to threehalogen atoms (preferably fluoro), (C₁-C₆)alkyl-(C═O)—, formyl,formamidyl, cyano, nitro, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C6-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₁-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)— (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—;

[0013] wherein said R² (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—, (C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)— (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0014] R³ is selected from the group consisting of (C₁-C₆)alkyl,(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl and(C₁-C₉)heterocyclic;

[0015] wherein each of said R³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl or (C₁-C₉)heterocyclic groups mayoptionally be substituted with one to three substituents independentlyselected from halo, amino, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano, nitro, —OCF₃, —CF₃, (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic,(C₆-C₁₀)aryloxy, (C₁-C₉)heteroaryloxy, (C₃-C₁₀)cycloalkoxy and(C₁-C₉)heterocyclic-O—; wherein each of said (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic or (C₁-C₉)heteroarylsubstituents may optionally be substituted with one to three moietiesindependently selected from halo, amino, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano, nitro, —OCF₃ and—CF₃; wherein said amino substituent or moiety may optionally besubstituted by one or two elements independently selected fromoptionally substituted (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heterocyclic and (C₁-C₉)heteroaryl, wherein said elements areoptionally substituted by halo, amino, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, —OCF₃ or —CF₃;

[0016] R⁴ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkyl-(C═O)— or (C₁-C₆)alkyl-O—(C═O)—;

[0017] R⁵ is hydrogen, halo (more preferably chloro or fluoro, mostpreferably fluoro), (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—, formyl, formamidyl, cyano, nitro,—CO₂H. (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, (C₆-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂—N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—,[(C₁-C₉)heteroaryl]₂—N—(C═O)—, [(C₁-C₉)heterocyclic]₂—N—(C═O)—,(C₁-C₆)alkoxyiminyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—,(C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—;

[0018] wherein said R⁵ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₂-Cg)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0019] R⁶ is hydrogen, halo (more preferably chloro or fluoro, mostpreferably fluoro), (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—, formyl, formamidyl, cyano, nitro,amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₁-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—;

[0020] wherein said R⁶ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0021] R⁷ is hydrogen, halo (preferably fluoro or chloro), hydroxy,mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one tothree halogen atoms (preferably fluoro), (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—,—CO₂H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-Cg)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, nitro, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—, (C₆-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂—N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—,[(C₁-C₉)heteroaryl]₂—N—(C═O)—, [(C₁-C₉)heterocyclic]₂—N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₈-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—;

[0022] wherein said R⁷ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)-, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆₉)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)-NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0023] R⁸ is hydrogen, halo (preferably fluoro or chloro), hydroxy,mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one tothree halogen atoms (preferably fluoro), (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—,—CO₂H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, nitro, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—, (C₃-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂—N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—,[(C₁-C₉)heteroaryl]₂—N—(C═O)—, [(C₁-C₉)heterocyclic]₂—N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—;

[0024] wherein said R⁸ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—N H—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0025] or the pharmaceutically acceptable salts of such compounds.

[0026] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methahesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0027] The invention also relates to base addition salts of formula I.The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (eg., potassium and sodium) and alkaline earthmetal cations (eg., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0028] The compounds of this invention include all stereoisomers (eg,cis and trans isomers) and all optical isomers of compounds of theformula I (eg., R and S enantiomers), as well as racemic, diastereomericand other mixtures of such isomers.

[0029] The compounds of the invention may also exist in differenttautomeric forms. This invention relates to all tautomers of formula I.

[0030] The compounds of this invention may contain olefin-like doublebonds. When such bonds are present, the compounds of the invention existas cis and trans configurations and as mixtures thereof.

[0031] As used herein, the term “alkyl,” as well as the alkyl moietiesof other groups referred to herein (eg, alkoxy), may be linear orbranched (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, secondary-butyl, tertiary-butyl), and they may also be cyclic(eg., cyclopropyl or cyclobutyl); optionally substituted by 1 to 3suitable substituents as defined below such as fluoro, chloro,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl. The phrase “each of said alkyl” as usedherein refers to any of the preceding alkyl moieties within a group suchalkoxy, alkenyl or alkylamino. Preferred alkyls include (C₁-C₄)alkyl,most preferably methyl.

[0032] As used herein, the term “cycloalkyl” refers to a mono orbicyclic carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl, etc.); optionally containing 1-2 double bonds andoptionally substituted by 1 to 3 suitable substituents as defined belowsuch as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl, more preferablyfluoro, chloro, methyl, ethyl and methoxy. The phrase “each of saidalkyl” as used herein refers to any of the preceding alkyl moietieswithin a group such alkoxy, alkenyl or alkylamino. Preferred alkylsinclude

[0033] As used herein, the term “halogen” includes fluoro, chloro, bromoor iodo or fluoride, chloride, bromide or iodide.

[0034] As used herein, the term “mercapto” refers to the group —SH.

[0035] As used herein, the term “halo-substituted alkyl” refers to analkyl radical as described above substituted with one or more halogensincluded, but not limited to, chloromethyl, dichloromethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, andthe like; optionally substituted by 1 to 3 suitable substituents asdefined below such as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

[0036] As used herein, the term “alkenyl” means straight or branchedchain unsaturated radicals of 2 to 6 carbon atoms, including, but notlimited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined below such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

[0037] As used herein, the term “(C₂-C₆)alkynyl” is used herein to meanstraight or branched hydrocarbon chain radicals having one triple bondincluding, but not limited to, ethynyl, propynyl, butynyl, and the like;optionally substituted by 1 to 3 suitable substituents as defined belowsuch as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

[0038] As used herein, the term “alkoxyiminyl” refers to a group of theformula —C═N—O—R, wherein R is alkyl or aryl optionally substituted witha suitable substituent. Examples of such groups are methoxyiminyl andphenoxyiminyl.

[0039] As used herein, the term “carbonyl” (as used in phrases such asalkylcarbonyl or alkoxycarbonyl) refers to the joinder of the >C═Omoiety to a second moiety such as an alkyl or amino group (i.e. an amidogroup). Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refers to an alkylcarbamate group. The carbonyl group is also equivalently defined hereinas (C═O). Alkylcarbonylamino refers to groups such as acetamide.

[0040] As used herein, the term “(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—”as used herein, refers to a disubstituted amide group of the formula

[0041] As used herein, the term “aryl” means aromatic radicals such asphenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionallysubstituted by 1 to 3 suitable substituents as defined below such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl, more preferablyfluoro, chloro, methyl, ethyl and methoxy.

[0042] As used herein, the term “heteroaryl” refers to an aromaticheterocyclic group usually with one heteroatom selected from O, S and Nin the ring. In addition to said heteroatom, the aromatic group mayoptionally have up to four N atoms in the ring. For example, heteroarylgroup includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl,furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl,1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl),pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl(e.g., 1,3,4-thiadiazolyl), tetrazole, quinolyl, isoquinolyl,benzothienyl, benzofuryl, indolyl, and the like; optionally substitutedby 1 to 3 suitable substituents as defined below such as fluoro, chloro,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl, more preferably fluoro, chloro, methyl,ethyl and methoxy. Particularly preferred heteroaryl groups includepyridyl, thienyl, furyl, thiazolyl and pyrazolyl (these heteroaryls aremost preferred of the R⁴ heteroaryls).

[0043] The term “heterocyclic” as used herein refers to a cyclic groupcontaining 1-9 carbon atoms and 1-4 hetero atoms selected from N, O, Sor NR′. Examples of monocyclic saturated or partially saturated ringsystems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl,pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl,piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,thiomorpholine, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,tetrahydrothiadiazine, morpholine, 1,2-tetrahydrodiazin-2-yl,1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin4-yl and thelike; optionally substituted by 1 to 3 suitable substituents as definedbelow such as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl, morepreferably fluoro, chloro, methyl, ethyl and methoxy.

[0044] As used herein, the term “a suitable substituent” is intended tomean a chemically and pharmaceutically acceptable functional group i.e.,a moiety that does not negate the inhibitory activity of the inventivecompounds. Such suitable substituents may be routinely selected by thoseskilled in the art. Illustrative examples of suitable substituentsinclude, but are not limited to halo groups, perfluoroalkyl groups,perfluoroalkoxy groups, alkyl groups, hydroxy groups, oxo groups,mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroarylgroups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkylgroups, aralkoxy or heteroaralkoxy groups, —CO₂H groups, amino groups,alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups,alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonylgroups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonylgroups, an arylsulfonyl groups and the like.

[0045] An embodiment of the present invention includes compounds offormula I, referred to as the Arylsulfonyl Group of compounds, wherein Xand Y are both carbon. Another embodiment of the present inventionincludes compounds of formula I, referred to as thePyridin-2-yl-sulfonyl Group of compounds, wherein X is nitrogen and Y iscarbon. Another embodiment of the present invention includes compoundsof formula I, referred to as the Pyridin-3-yl-sulfonyl Group ofcompounds, wherein Y is nitrogen and X is carbon. Another embodiment ofthe present invention includes compounds of formula I, referred to asthe Pyridazin-2-yl-sulfonyl Group of compounds, wherein X and Y are bothnitrogen.

[0046] Another embodiment of the present invention includes compounds offormula I, referred to as the Pyrazole-ether Group of compounds wherein“A” is —O—. Another embodiment of the present invention includescompounds of formula I, referred to as the Pyrazole-thioether Group ofcompounds, wherein “A” is —S—. Another embodiment of the presentinvention includes compounds of formula I, referred to as thePyrazole-sulfoxide Group of compounds, wherein “A” is >S═O. Anotherembodiment of the present invention includes compounds of formula I,referred to as the Pyrazole-sulfone Group of compounds, wherein “A” is>SO₂. Another embodiment of the present invention includes compounds offormula I, referred to as the Pyrazole-amine Group of compounds, wherein“A” is >NR⁴.

[0047] Subgeneric embodiments of the present invention of theArylsulfonyl Group of compounds are expressly contemplated by thepresent invention. Such subgeneric embodiments within the ArylsulfonylGroup of compounds include the Arylsulfonyl Group in combination witheach of the A and R³ groups (i.e. 5-Alkylether-1-Arylsulfonyl-PyrazoleGroup, 5-Arylether-1-Arylsulfonyl-Pyrazole Group,5-Cycloalkylether-1-Arylsulfonyl-Pyrazole Group,5-Heteroarylether-1-Arylsulfonyl-Pyrazole Group5-Heterocyclicether-1-Arylsulfonyl-Pyrazole Group,5-Alkylthioether-1-Arylsulfonyl-Pyrazole Group,5-Arylthioether-1-Arylsulfonyl-Pyrazole Group,5-Cycloalkylthioether-1-Arylsulfonyl-Pyrazole Group,5-Heteroarylthioether-1-Arylsulfonyl-Pyrazole Group,5-Heterocyclicthioether-1-Arylsulfonyl-Pyrazole Group,5-Alkylsulfoxide-1-Arylsulfonyl-Pyrazole Group,5-Arylsulfoxide-1-Arylsulfonyl Pyrazole Group,5-Cycloalkylsulfoxide-1-Arylsulfonyl-Pyrazole Group,5-Heteroarylsulfoxide-1-Arylsulfonyl-Pyrazole Group,5-Heterocyclicsulfoxide-1-Arylsulfonyl Pyrazole Group,5-Alkylsulfone-1-Arylsulfonyl-Pyrazole Group,5-Arylsulfone-1-Arylsulfonyl-Pyrazole Group, 5-Cycloalkylsulfone-1Arylsulfonyl-Pyrazole Group, 5-Heteroarylsulfone-1-Arylsulfonyl-PyrazoleGroup, 5-Heterocyclicsulfone-1-Arylsulfonyl-Pyrazole Group,5-Alkylamine-1-Arylsulfonyl-Pyrazole Group,5-Arylamine-1-Arylsulfonyl-Pyrazole Group,5-Cycloalkylamine-1-Arylsulfonyl-Pyrazole Group,5-Heteroarylamine-1-Arylsulfonyl-Pyrazole Group and the5-Heterocyclicamine-1-Arylsulfonyl-Pyrazole Group).

[0048] Subgeneric embodiments of the present invention of thePyridin-2-yl-sulfonyl Group of compounds are expressly contemplated bythe present invention. Such subgeneric embodiments within thePyridin-2-yl-sulfonyl Group of compounds include thePyridin-2-yl-sulfonyl Group in combination with each of the A and R³groups (i.e. 5-Alkylether-1-Pyridin-2-yl-Pyrazole Group,5-Arylether-1-Pyridin-2-yl-Pyrazole Group,5-Cycloalkylether-1-Pyridin-2-yl-Pyrazole Group,5-Heteroarylether-1-Pyridin-2-yl-Pyrazole Group5-Heterocyclicether-1-Pyridin-2-yl-Pyrazole Group,5-Alkylthioether-1-Pyridin-2-yl-Pyrazole Group,5-Arylthioether-1-Pyridin-2-yl-Pyrazole Group,5-Cycloalkylthioether-1-Pyridin-2-yl-Pyrazole Group,5-Heteroarylthioether-1-Pyridin-2-yl-Pyrazole Group,5-Heterocyclicthioether-1-Pyridin-2-yl-Pyrazole Group,5-Alkylsulfoxide-1-Pyridin-2-yl-Pyrazole Group,5-Arylsulfoxide-1-Pyridin-2-yi Pyrazole Group,5-Cycloalkylsulfoxide-1-Pyridin-2-yl-Pyrazole Group,5-Heteroarylsulfoxide-1-Pyridin-2-yl-Pyrazole Group,5-Heterocyclicsulfoxide-1-Pyridin-2-yl Pyrazole Group,5-Alkylsulfone-1-Pyridin-2-yl-Pyrazole Group,5-Arylsulfone-1-Pyridin-2-yl-Pyrazole Group,5-Cycloalkylsulfone-1-Pyridin-2-yl-Pyrazole Group,5-Heteroarylsulfone-1-Pyridin-2-yl-Pyrazole Group,5-Heterocyclicsulfone-1-Pyridin-2-yl-Pyrazole Group,5-Alkylamine-1-Pyridin-2-yl-Pyrazole Group,5-Arylamine-1-Pyridin-2-yl-Pyrazole Group,5-Cycloalkylamine-1-Pyridin-2-yl-Pyrazole Group,5-Heteroarylamine-1-Pyridin-2-yl-Pyrazole Group and the5-Heterocyclicamine-1-Pyridin-2-yl-Pyrazole Group).

[0049] Subgeneric embodiments of the present invention of thePyridin-3-yl-sulfonyl Group of compounds are expressly contemplated bythe present invention. Such subgeneric embodiments within thePyridin-3-yl-sulfonyl Group of compounds include thePyridin-3-yl-sulfonyl Group in combination with each of the AR³ (i.e.5-Alkylether-1-Pyridin-3-yl-Pyrazole Group,5-Arylether-1-Pyridin-3-yl-Pyrazole Group,5-Cycloalkylether-1-Pyridin-3-yl-Pyrazole Group,5-Heteroarylether-1-Pyridin-3-yl-Pyrazole Group5-Heterocyclicether-1-Pyridin-3-yl-Pyrazole Group,5-Alkylthioether-1-Pyridin-3-yl-Pyrazole Group,5-Arylthioether-1-Pyridin-3-yl-Pyrazole Group,5-Cycloalkylthioether-1-Pyridin-3-yl-Pyrazole Group,5-Heteroarylthioether-1-Pyrid in-3-yl-Pyrazole Group,5-Heterocyclicthioether-1-Pyridin-3-yl-Pyrazole Group,5-Alkylsulfoxide-1 Pyridin-3-yl-Pyrazole Group,5-Arylsulfoxide-1-Pyridin-3-yl Pyrazole Group,5-Cycloalkylsulfoxide-1-Pyridin-3-yl-Pyrazole Group,5-Heteroarylsulfoxide-1-Pyridin-3-yl-Pyrazole Group,5-Heterocyclicsulfoxide-1-Pyridin-3-yl Pyrazole Group,5-Alkylsulfone-1-Pyridin-3-yl-Pyrazole Group,5-Arylsulfone-1-Pyridin-3-yl-Pyrazole Group,5-Cycloalkylsulfone-1-Pyridin-3-yl-Pyrazole Group,5-Heteroarylsulfone-1-Pyridin-3-yl-Pyrazole Group,5-Heterocyclicsulfone-1-Pyridin-3-yl-Pyrazole Group,5-Alkylamine-1-Pyridin-3-yl-Pyrazole Group,5-Arylamine-1-Pyridin-3-yl-Pyrazole Group,5-Cycloalkylamine-1-Pyridin-3-yl-Pyrazole Group,5-Heteroarylamine-1-Pyridin-3-yl-Pyrazole Group and the5-Heterocyclicamine-1-Pyridin-3-yl-Pyrazole Group).

[0050] Subgeneric embodiments of the present invention of thePyridazin-2-yl-sulfonyl Group of compounds are expressly contemplated bythe present invention. Such subgeneric embodiments within thePyridazin-2-yl-sulfonyl Group of compounds include thePyridazin-2-yl-sulfonyl Group in combination with each of the AR³ groups(i.e. 5-Alkylether-1-Pyridazin-2-yl-Pyrazole Group,5-Arylether-1-Pyridazin-2-yl-Pyrazole Group, 5-Cycloalkylether-1-15.Pyridazin-2-yl-Pyrazole Group,5-Heteroarylether-1-Pyridazin-2-yl-Pyrazole Group5-Heterocyclicether-1-Pyridazin-2-yl-Pyrazole Group,5-Alkylthioether-1-Pyridazin-2-yl-Pyrazole Group,5-Arylthioether-1-Pyridazin-2-yl-Pyrazole Group,5-Cycloalkylthioether-1-Pyridazin-2-yl-Pyrazole Group,5-Heteroarylthioether-1-Pyridazin-2-yl-Pyrazole Group,5-Heterocyclicthioether-1-Pyridazin-2-yl-Pyrazole Group,5-Alkylsulfoxide-1-Pyridazin-2-yl-Pyrazole Group,5-Arylsulfoxide-1-Pyridazin-2-yl Pyrazole Group,5-Cycloalkylsulfoxide-1-Pyridazin-2-yl-Pyrazole Group,5-Heteroarylsulfoxide-1-Pyridazin-2-yl-Pyrazole Group,5-Heterocyclicsulfoxide-1-Pyridazin-2-yl Pyrazole Group,5-Alkylsulfone-1-Pyridazin-2-yl-Pyrazole Group,5-Arylsulfone-1-Pyridazin-2-yl-Pyrazole Group,5-Cycloalkylsulfone-1-Pyridazin-2-yl-Pyrazole Group,5-Heteroarylsulfone-1-Pyridazin-2-yl-Pyrazole Group,5-Heterocyclicsulfone-1-Pyridazin-2-yl-Pyrazole Group,5-Alkylamine-1-Pyridazin-2-yl-Pyrazole Group,5-Arylamine-1-Pyridazin-2-yl-Pyrazole Group,5-Cycloalkylamine-1-Pyridazin-2-yl-Pyrazole Group,5-Heteroarylamine-0.1-Pyridazin-2-yl-Pyrazole Group and the5-Heterocyclicamine-1-Pyridazin-2-yl-Pyrazole Group).

[0051] Preferred compounds of this invention are those of the formula(I) wherein X is CR⁷ and Y is nitrogen.

[0052] Other preferred compounds of this invention are those of theformula (I) wherein X is nitrogen and Y is CR⁸.

[0053] Other preferred compounds of this invention are those of theformula (I) wherein X is CR⁷ and Y is CR⁸, more preferably wherein R⁷and R⁸ are each independently selected from hydrogen, (C₁-C₄)alkyl andhalogen, more preferably hydrogen and methyl.

[0054] Other preferred compounds of this invention are those of theformula (I) wherein R¹ is (C₁-C₆)alkyl (preferably methyl) or —NH₂.

[0055] Other preferred compounds of this invention are those of theformula (I) wherein A is Other preferred compounds of this invention arethose of the formula (I) wherein A is —S—.

[0056] Other preferred compounds of this invention are those of theformula (I) wherein A is >NR⁴.

[0057] Other preferred compounds of this invention are those of theformula (I) wherein R³ is optionally substituted (C₁-C₆)alkyl or(C₃-C₁₀)cycloalkyl, more preferably wherein said substituents areselected from (C₁-C₆)alkoxy, amino, (C₆-C₁₀)aryl, (C₁-C₉)heteroaryl,(C₃-C₁₀)cycloalkyl and (C₁-C₉)heterocyclic, most preferably wherein saidsubstituents include (C₃-C₁₀)cycloalkyl or (C₁-C₉)heterocyclic.

[0058] Other preferred compounds of this invention are those of theformula (I) wherein R⁵ is hydrogen, halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxyiminyl, (C₁-C₆)alkoxy-(C═O)—, (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₁-C₉)heterocyclic, formyl or cyano, more preferablyhydrogen, halo, (C₁-C₆)alkyl or cyano, most preferably hydrogen, methyl,ethyl or cyano.

[0059] Other preferred compounds of this invention are those of theformula (I) wherein R⁶ is amino, (C₁-C₆)alkoxy, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl(S═O)—, (C₁-C₆)alkyl-SO₂—, cyano or (C₁-C₆)alkyl optionallysubstituted with one to three halo substituents, more preferably —CF₃ or—CHF₂.

[0060] Other preferred compounds of this invention are those of theformula (I) wherein R⁷ and R⁸ are each hydrogen.

[0061] Examples of specific preferred compounds of the formula I are thefollowing:

[0062]2-(5-Isobutoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0063]2-[5-(1-Ethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0064]2-(5-Cyclopentyloxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0065]2-Fluoro-4-(5-isopropoxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0066]2-Fluoro-4-(5-isobutoxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0067]2-Fluoro-4-(5-cyclopentyloxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0068]1-(5-Methanesulfonyl-pyridin-2-yl)-5-cyclohexylsulfanyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0069]1-(5-Methanesulfonyl-pyridin-2-yl)-5-isopropylamino-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0070]5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0071]5-(Cyclopropylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0072]5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehydeO-methyl-oxime;

[0073] 5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0074]5-(Cyclohexylmethylamino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0075]1-(5-Methanesulfonyl-pyridin-2-yl)-5-isopropylsulfanyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;and

[0076]1-(5-Methanesulfonyl-pyridin-2-yl)-5-isopropylamino-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde.

[0077] Other compounds of formula I include the following:

[0078]2-(5-isopropoxy-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0079]2-fluoro-4-(5-isopropoxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0080]2-(5-isopropoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0081]2-(5-Isopropoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0082]2-(5-Cyclohexyloxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0083]5-Methanesulfonyl-2-(5-methoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine;

[0084]2-(5-Ethoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0085]5-Methanesulfonyl-2-(5-propoxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine2-(5-Butoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0086]5-Methanesulfonyl-2-(5-pentyloxy-3-trifluoromethyl-pyrazol-1-yl)-pyridine;

[0087]2-(5-sec-Butoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0088]2-(5-Allyloxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0089]2-(5-Cyclopropylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0090]2-(5-Cyclobutoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0091]2-(5-Cyclobutylmethoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0092]2-[5-(3-Chloro-benzyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0093]2-[5-(3-Fluoro-benzyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0094]5-Methanesulfonyl-2-[3-trifluoromethyl-5-(3-trifluoromethyl-benzyloxy)-pyrazol-1-yl]-pyridine;

[0095]2-(5-Benzyloxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0096]2-[5-(2-pyridyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0097]2-[5-(3-pyridyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0098]2-[5-(4-pyridyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0099]5-Methanesulfonyl-2-[5-(naphthalen-1-ylmethoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine;

[0100]2-[2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yloxymethyl]-quinoline;

[0101]5-Methanesulfonyl-2-[5-(4-methyl-benzyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine;

[0102]2-[5-(4-Chloro-benzyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;5-Methanesulfonyl-2-[5-(2-methyl-benzyloxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine;

[0103]2-[5-(2-Fluoro-benzyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0104]2-[5-(2-Chloro-benzyloxy)-3-trifluoromethyl-pyrazol-1-yl]-5-methanesulfonyl-pyridine;

[0105]5-Methanesulfonyl-2-[5-(2-methoxy-benzyloxy)-3-trifluoromethyl-pyrazol1-yl]-pyridine;2-(5-Isopropoxy-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0106]2-Fluoro-4-(5-cyclohexyloxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0107] 4-(5-Allyloxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0108]4-(5-Benzyloxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0109]5-Isobutoxy-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0110]5-Cyclopentyloxy-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0111]2-(4-Chloro-5-isobutoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0112]2-(4-Chloro-5-cyclopentyloxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine;

[0113]2-Fluror-4-(4-formyl-5-isobutoxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0114]2-Fluror-4-(4-formyl-5-cyclopentyloxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide;

[0115]4-(4-Chloro-5-isobutoxy-3-trifluoromethyl-pyrazol-1-yl)-2-fluoro-benzenesulfonamide;4-(4-Chloro-5-cyclopentyloxy-3-trifluoromethyl-pyrazol-1-yl)-2-fluoro-benzenesulfonamide;

[0116]5-Cyclopentylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbaldehyde;

[0117]5-Cyclohexylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbaldehyde;

[0118]3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methylethylamino)-1H-pyrazole-4-carbaldehyde;

[0119]5-sec-Butylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbaldehyde;

[0120]5-Benzylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbaldehyde;

[0121]3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-1H-pyrazole-4-carbaldehyde;

[0122]3-Difluoromethyl-5-(isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbaldehyde;5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbaldehyde;

[0123]5-Cyclopentylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

[0124]5-Cyclohexylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

[0125]3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methylethylamino)-1H-pyrazole-4-carbonitrile;

[0126]5-sec-Butylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;5-Benzylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

[0127]3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-1H-pyrazole-4-carbonitrile;

[0128]3-Difluoromethyl-5-(isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

[0129]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;

[0130]1-[5-Cyclopentylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone;

[0131]1-[5-Cyclohexylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone;

[0132]1-[3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methyl-ethylamino)-1H-pyrazol-4-yl]-ethanone;

[0133]1-[5-sec-Butylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone;

[0134]1-[5-Benzylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone;

[0135]1-[3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-1H-pyrazol-4-yl]-ethanone;1-[3-Difluoromethyl-5-(isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone;

[0136]1-[5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone;

[0137]5-Cyclopentylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carboxylic;

[0138]5-sec-Butylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carboxylic;

[0139]5-Benzylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carboxylic;

[0140]3-Difluoromethyl-5-(isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carboxylic;

[0141]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carboxylic;

[0142]5-Cyclopentylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carboxylic;

[0143]Cyclopentyl-[5-difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)-2H-pyrazol-3-yl]-amine;

[0144]Cyclohexylmethyl-[5-difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)-2H-pyrazol-3-yl]-amine;

[0145]Cyclopentyl-[5-difluoromethyl-2-(5-methanesulfonylpyridin-2-yl)₄-methyl-2H-pyrazol-3-yl]-amine;

[0146][5-Difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)₄-methyl-2H-pyrazol-3-yl]-(2-methoxy-1-methyl-ethyl)-amine;

[0147]sec-Butyl-[5-difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)₄-methyl-2H-pyrazol-3-yl]-amine;

[0148]Benzyl-[5-difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)₄-methyl-2H-pyrazol-3-yl]-amine;

[0149][5-Difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)₄-methyl-2H-pyrazol-3-yl]-(2-methyl-allyl)-amine;

[0150][5-Difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)₄-methyl-2H-pyrazol-3-yl]-isopropyl-methyl-amine;

[0151]Cyclohexylmethyl-[5-difluoromethyl-2-(5-methanesulfonyl-pyridin-2-yl)₄-methyl-2H-pyrazol-3-yl]-amine;

[0152][5-Cyclopentylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-methanol;

[0153][3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methylethylamino)-1H-pyrazol-4-yl]-methanol;

[0154][5-sec-Butylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-methanol;

[0155][5-Benzylamino-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-methanol;

[0156][3-Difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-1H-pyrazol-4-yl]-methanol;

[0157][3-Difluoromethyl-5-(isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-methanol;

[0158][5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazol-4-yl]-methanol;

[0159] 5-Cyclohexylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0160]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0161]5-sec-Butylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0162]5-Benzylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0163]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0164]5-(Isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl1H-pyrazole-4-carbaldehyde;

[0165]5-(Cyclohexylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0166]5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0167]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0168]5-sec-Butylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0169]5-Benzylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0170]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0171]5-(Isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0172]5-(Cyclohexylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0173]1-[5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;1-[1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0174]1-[5-sec-Butylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0175]1-[5-Benzylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0176]-[1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0177]1-[5-(Isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0178]1-[5-(Cyclohexylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0179]5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0180]5-Cyclohexylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0181]5-Benzylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0182]1-(5-Methanesulfonyl-pyridin-2-y)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0183]5-(Isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0184]5-(Cyclohexylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0185]5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0186]5-sec-Butylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0187]5-Benzylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0188]5-(Cyclohexylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0189] Cyclopentyl-[2-(5-methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0190][2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-(2-methoxy-1-methyl-ethyl)-amine;

[0191]sec-Butyl-[2-(5-methanesulfonyl-pyridin-2-yl)₅-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0192]Benzyl-[2-(5-methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0193][2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-(2-methyl-allyl)amine;

[0194]Isopropyl-[2-(5-methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-methyl-amine;

[0195]Cyclohexylmethyl-[2-(5-methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0196]Cyclopentyl-[2-(5-methanesulfonyl-pyridin-2-yl)₄-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0197]Cyclohexyl-[2-(5-methanesulfonyl-pyridin-2-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0198][2-(5-Methanesulfonyl-pyridin-2-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-(2-methoxy-1-methyl-ethyl)-amine;

[0199]sec-Butyl-[2-(5-methanesulfonyl-pyridin-2-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0200]Benzyl-[2-(5-methanesulfonyl-pyridin-2yl)-4-methyl-5trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0201][2-(5-Methanesulfonyl-pyridin-2-yl)₄-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-(2-methyl-allyl)-amine;

[0202]Isopropyl-[2-(5-methanesulfonyl-pyridin-2-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-methyl-amine;

[0203]Cyclohexylmethyl-[2-(5-methanesulfonyl-pyridin-2-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0204][5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0205][5-Cyclohexylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0206][1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0207][5-sec-Butylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0208][5-Benzylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0209][1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0210][5-(Isopropyl-methyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0211][5-(Cyclohexylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0212]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carbaldehyde;

[0213]5-Benzylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carbaldehyde;

[0214]3-Difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-(2-methyl-allylamino)-1H-pyrazole-4-carbaldehyde;

[0215]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carbaldehyde;

[0216]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carbonitrile;

[0217]3-Difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methylethylamino)-1H-pyrazole-4-carbonitrile;

[0218]5-Benzylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carbonitrile;

[0219]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carbonitrile;

[0220]1-[5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazol-4-yl]-ethanone;

[0221]1-[5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazol-4-yl]-ethanone;

[0222]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carboxylic;

[0223]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carboxylic

[0224]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carboxylic;

[0225]5-sec-Butylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carboxylic;

[0226]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazole-4-carboxylic;

[0227]Cyclopentyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl)-2H-pyrazol-3-yl]-amine;

[0228]Cyclopentyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-2H-pyrazol-3-yl]-amine;

[0229][5-Difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-2H-pyrazol-3-yl]-(2-methoxy-1-methyl-ethyl)-amine;

[0230]sec-Butyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl)₄-methyl-2H-pyrazol-3-yl]-amine;

[0231]Benzyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl>4-methyl-2H-pyrazol-3-yl]-amine;

[0232][5-Difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-2H-pyrazol-3-yl]-(2-methyl-allyl)-amine;[5-Difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-2H-pyrazol-3-yl]-isopropyl-methyl-amine;

[0233]Cyclohexylmethyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-2H-pyrazol-3-yl]-amine;

[0234][5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0235][3-Difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methylethylamino)-1H-pyrazol-4-yl]-methanol;

[0236][5-sec-Butylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0237][5-Benzylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0238][3-Difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-5-(2-methyl-allylamino)-1H-pyrazol-4-yl]-methanol;

[0239][3-Difluoromethyl-5-(isopropyl-methyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0240][5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0241]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0242]1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0243]5-sec-Butylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0244]5-Benzylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0245]1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0246]5-(Isopropyl-methyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0247]5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0248]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0249]5-Cyclohexylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0250]1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0251]5-sec-Butylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0252]5-Benzylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0253]1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0254]5-(Isopropyl-methyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0255]5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0256]1-[5-Cyclopentylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0257]1-[1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0258]1-[5-sec-Butylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0259]1-[5-Benzylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0260]1-[1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0261]1-[5-(Isopropyl-methyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0262]1-[5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0263]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0264]1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0265]5-sec-Butylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0266]5-Benzylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0267]1-(6-Methansulfonyl-pyridin-3-yl)-5-(2-methyl-allylamino)-3-trifluoromethy-1H-pyrazole-4-carboxylic;

[0268]5-(Isopropyl-methyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0269]5-(Cyclohexylmethyl-amino)1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0270]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0271]1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methyl-ethylamino)₃-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0272]5-sec-Butylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0273]5-Benzylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0274]1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0275]5-(Isopropyl-methyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0276]5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0277]Cyclopentyl-[2-(6-methanesulfonyl-pyridin-3-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0278]Cyclohexylmethyl-[2-(6-methanesulfonyl-pyridin-3-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0279] Cyclopentyl-[2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0280][2-(6-Methanesulfonyl-pyridin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-(2-methoxy-1-methyl-ethyl)-amine;

[0281]sec-Butyl-[2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0282]Benzyl-[2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0283][2-(6-Methanesulfonyl-pyridin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-(2-methyl-allyl)-amine;

[0284]Isopropyl-[2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-methyl-amine;

[0285]Cyclohexylmethyl-[2-(6-methanesulfonyl-pyridin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0286][5-Cyclopentylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0287][1-(6-Methanesulfonyl-pyridin-3-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0288][5-sec-Butylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0289][5-Benzylamino-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0290][5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0291]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carbaldehyde;

[0292]5-Benzylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carbaldehyde;

[0293]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carbaldehyde;

[0294]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carbonitrile;

[0295]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carbonitrile;

[0296]1-[5-Cyclohexylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)1H-pyrazol-4-yl]-ethanone;

[0297]1-(5-Benzylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazol-4-yl]-ethanone;

[0298]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic;

[0299]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic;

[0300]5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic;

[0301]5-(Cyclohexylmethyl-amino)-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazole-4-carboxylic,

[0302]Cyclopentyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridazin-3-yl)-2H-pyrazol-3-yl]-amine,

[0303]Cyclohexylmethyl-[5-difluoromethyl-2(6-methanesulfonyl-pyridazin-3-yl)-2H-pyrazol-3-yl]-amine,

[0304]Cyclopentyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridazin-3-yl)-4-methyl-2H-pyrazol-3-yl]-amine,

[0305] Benzyl[5-difluoromethyl-2-(6-methanesulfonyl-pyridazin-3-yl)-4-methyl-2H-pyrazol-3-yl]-amine,

[0306]Cyclohexylmethyl-[5-difluoromethyl-2-(6-methanesulfonyl-pyridazin-3-yl)-4-methyl-2H-pyrazol-3-yl]-amine;

[0307][5-Cyclopentylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0308][5-sec-Butylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0309][5-Benzylamino-3-difluoromethyl-1-(6-methanesulfonyl-pyridazin-3-yl)-1H-pyrazol-4-yl]-methanol;

[0310]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0311]5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0312]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0313]5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0314]1-[5-Cyclopentylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0315]1-[1-(6-Methanesulfonyl-pyridazin-3-yl)-5-(2-methoxy-1-methyl-ethylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0316]1-[5-sec-Butylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0317]1-[5-Benzylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0318]1-[1-(6-Methanesulfonyl-pyridazin-3-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0319]1-[5-(Isopropyl-methyl-amino)-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0320]1-[5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-ethanone;

[0321]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0322]5-Cyclopentylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic;

[0323]Cyclopentyl-[2-(6-methanesulfonyl-pyridazin-3-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0324]sec-Butyl-[2-(6-methanesulfonyl-pyridazin-3-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0325]Cyclopentyl-[2-(6-methanesulfonyl-pyridazin-3-yl)₄-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0326]sec-Butyl-[2-(6-methanesulfonyl-pyridazin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0327]Benzyl-[2-(6-methanesulfonyl-pyridazin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0328][2-(6-Methanesulfonyl-pyridazin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-(2-methyl-allyl)-amine;

[0329]Cyclohexylmethyl-[2-(6-methanesulfonyl-pyridazin-3-yl)-4-methyl-5-trifluoromethyl-2H-pyrazol-3-yl]-amine;

[0330][5-Cyclopentylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0331]5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehydeO-methyl-oxime;

[0332]5-(Cyclohexylmethyl-amino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0333]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(2-methyl-allylamino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0334]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(4-methyl-cyclohexylamino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0335]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(methoxymethyl-methyl-amino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0336]5-Cyclohexylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0337]1-(5-Methanesulfonyl-pyridin-2-yl)-5-[(pyridin-2-ylmethyl)-amino]-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0338]5-(1-Ethyl-propylamino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0339]5-Benzylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0340]5-Cyclobutylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0341][5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;

[0342]5-Cyclopentylamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0343]1-(5-Methanesulfonyl-pyridin-2-yl)-5-(benzyl-methyl-amino)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde;

[0344]5-(Cyclohexylmethylamino)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;

[0345][5-Benzylamino-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol;and

[0346][5-(Cyclohexylmethyl-amino)-1-(6-methanesulfonyl-pyridazin-3-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-methanol.

[0347] The present invention relates to novel intermediates andprocesses of using compounds of the formula

[0348] wherein L′ is —OH, —SH, halo or —NHR⁴;

[0349] X is CR⁷ or N,

[0350] Y is CR⁸ or N;

[0351] R¹ is (C₁-C₆)alkyl or —NH₂;

[0352] R² is hydrogen, halo (more preferably chloro or fluoro, mostpreferably fluoro), hydroxy, mercapto, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy optionally substituted with one to threehalogen atoms (preferably fluoro), (C₁-C₆)alkyl-(C═O)—, formyl,formamidyl, cyano, nitro, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-Cg)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-Cg)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-Cg)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O), [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—;

[0353] wherein said R² (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-Cg)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-Cg)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0354] R³ is selected from the group consisting of (C₁-C₆)alkyl,(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl and(C₁-C₉)heterocyclic;

[0355] wherein each of said R³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl or (C₁-C₉)heterocyclic groups mayoptionally be substituted with one to three substituents independentlyselected from halo, amino, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano, nitro, —OCF₃, —CF₃, (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic,(C₆-C₁₀)aryloxy, (C₁-C₉)heteroaryloxy, (C₃-C₁₀)cycloalkoxy and(C₁-C₉)heterocyclic-O—; wherein each of said (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic or (C₁-C₉)heteroarylsubstituents may optionally be substituted with one to three moietiesindependently selected from halo, amino, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano, nitro, —OCF₃ and—CF₃; wherein said amino substituent or moiety may optionally besubstituted by one or two elements independently selected fromoptionally substituted (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heterocyclic and (C₁-C₉)heteroaryl, wherein said elements areoptionally substituted by halo, amino, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, —OCF₃ or —CF₃;

[0356] R⁴ is hydrogen or (C₁-C₆)alkyl;

[0357] R⁵ is hydrogen, halo (more preferably chloro or fluoro, mostpreferably fluoro), (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O), formyl, formamidyl, cyano, nitro,—CO₂H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C—O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, (C6-C₁₀)aryl-NH—(C=Oy,[(C₆-C₁₀)aryl]₂—N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—,[(C₁-C₉)heteroaryl]₂—N—(C═O)—, [(C₁-C₉)heterocyclic]₂—N—(C═O)—,(C₁-C₆)alkoxyiminyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—,(C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—;

[0358] wherein said R⁵ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-Cg)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₂-C₉)heteroaryl, (C₂-C₉)heteroaryloxy,(C₂-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₂-Cg)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—N H—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0359] R⁶ is hydrogen, halo (more preferably chloro or fluoro, mostpreferably fluoro), (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—, formyl, formamidyl, cyano, nitro,amino, (C₁-C₆)alkylamino; [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—;

[0360] wherein said R⁶ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)O—,(C₁-Cg)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-Cg)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,((C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₁-C₁₀)aryl, (C₈-C₁₀)aryloxy,(C₁-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—,

[0361] R⁷ is hydrogen, halo (preferably fluoro or chloro), hydroxy,mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one tothree halogen atoms (preferably fluoro), (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-(C═O)—O—,—CO₂H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O), H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O),[(C₁-C₆)alkyl]₂—N—(C═O)—, nitro, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—, (C₆-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂—N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-N H—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—,[(C₁-C₉)heteroaryl]₂—N—(C═O)—, [(C₁-C₉)heterocyclic]₂—N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C, —C6)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—;

[0362] wherein said R⁷ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O), (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O), (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—, NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0363] R⁸ is hydrogen, halo (preferably fluoro or chloro), hydroxy,mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionally substituted with one tothree halogen atoms (preferably fluoro), (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—, (C₁-C₆)alkyl-(C═OF O—,—CO₂H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(Cr-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, nitro, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—, (C₆-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂—N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—,[(C₁-C₉)heteroaryl]₂—N—(C═O)—, [(C₁-C₉)heterocyclic]₂—N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—;

[0364] wherein said R⁸ (C₁-C₆)alkyl group may optionally be substitutedwith one to three substituents independently selected from halo,hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂—N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂—N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—;

[0365] and salts of such compounds.

[0366] The present invention also relates to a pharmaceuticalcomposition (i.e. for veterinary and human use) for the treatment of acondition selected from the group consisting of arthritis (includingosteoarthritis, degenerative joint disease, spondyloarthropathies, goutyarthritis, systemic lupus erythematosus, juvenile arthritis andrheumatoid arthritis), fever (including rheumatic fever and feverassociated with influenza and other viral infections), common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer (such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer;hematopoietic malignancies including leukemias and lymphomas; Hodgkin'sdisease; aplastic anemia, skin cancer and familiar adenomatouspolyposis), tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock animals) and septic shock in a mammal,preferably a human, cat, livestock animal or a dog, comprising an amountof a compound of formula I or a pharmaceutically acceptable salt thereofeffective in such treatment and a pharmaceutically acceptable carrier.

[0367] The present invention also relates to a pharmaceuticalcomposition for the treatment of a disorder or condition that can betreated by selectively inhibiting COX-2 in a mammal, preferably a human,cat, livestock animal or dog, comprising a COX-2 selective inhibitingeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

[0368] The present invention also relates to a method for treating acondition selected from the group consisting of arthritis (includingosteoarthritis, degenerative joint disease, spondyloarthropathies, goutyarthritis, systemic lupus erythematosus, juvenile arthritis andrheumatoid arthritis), fever (including rheumatic fever and feverassociated with influenza and other viral infections), common cold,dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn'sdisease, emphysema, acute respiratory distress syndrome, asthma,bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease,organ transplant toxicity, cachexia, allergic reactions, allergiccontact hypersensitivity, cancer (such as solid tumor cancer includingcolon cancer, breast cancer, lung cancer and prostrate cancer;hematopoietic malignancies including leukemias and lymphomas; Hodgkin'sdisease; aplastic anemia, skin cancer and familiar adenomatouspolyposis), tissue ulceration, peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis (including atherosclerotic plaquerupture), aortic aneurysm (including abdominal aortic aneurysm and brainaortic aneurysm), periarteritis nodosa, congestive heart failure,myocardial infarction, stroke, cerebral ischemia, head trauma, spinalcord injury, neuralgia, neuro-degenerative disorders (acute andchronic), autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain (includinglow back and neck pain, headache and toothache), gingivitis, cerebralamyloid angiopathy, nootropic or cognition enhancement, amyotrophiclateral sclerosis, multiple sclerosis, ocular angiogenesis, cornealinjury, macular degeneration, conjunctivitis, abnormal wound healing,muscle or joint sprains or strains, tendonitis, skin disorders (such aspsoriasis, eczema, scleroderma and dermatitis), myasthenia gravis,polymyositis, myositis, bursitis, burns, diabetes (including types I andII diabetes, diabetic retinopathy, neuropathy and nephropathy), tumorinvasion, tumor growth, tumor metastasis, corneal scarring, scleritis,immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats),sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders(preferably in livestock animals) and septic shock in a mammal,preferably a human, cat; livestock animal or a dog, comprisingadministering to said mammal an amount of a compound of formula I or apharmaceutically acceptable salt thereof effective in treating such acondition.

[0369] The present invention also relates to a method for treating adisorder or condition that can be treated or prevented by selectivelyinhibiting COX-2 in a mammal, preferably a human, cat, livestock animalor a dog, comprising administering to a mammal requiring such treatmenta COX-2 selective inhibiting effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof.

[0370] This invention also relates to a method of or a pharmaceuticalcomposition for treating inflammatory processes and diseases comprisingadministering a compound of formula I of this invention or its salt to amammal including a human, cat, livestock animal or dog, wherein saidinflammatory processes and diseases are defined as above, and saidinhibitory compound is used in combination with one or more othertherapeutically active agents under the following conditions:

[0371] A.) where a joint has become seriously inflamed as well asinfected at the same time by bacteria, fungi, protozoa, and/or virus,said inhibitory compound is administered in combination with one or moreantibiotic, antifungal, antiprotozoal, and/or antiviral therapeuticagents;

[0372] B.) where a multi-fold treatment of pain and inflammation isdesired, said inhibitory compound is administered in combination withinhibitors of other mediators of inflammation, comprising one or moremembers independently selected from the group consisting essentially of:

[0373] (1) NSAID's;

[0374] (2) H₁-receptor antagonists;

[0375] (3) kinin-B₁- and B₂-receptor antagonists;

[0376] (4) prostaglandin inhibitors selected from the group consistingof PGD-, PGF-PGI₂-, and PGE-receptor antagonists;

[0377] (5), thromboxane A₂ (TXA₂—) inhibitors;

[0378] (6) 5-, 12- and 15-lipoxygenase inhibitors;

[0379] (7) leukotriene LTC₄-, LTD₄/LTE₄-, and LTB₄-inhibitors;

[0380] (8) PAF-receptor antagonists;

[0381] (9) gold in the form of an aurothio group together with one ormore hydrophilic groups;

[0382] (10) immunosuppressive agents selected from the group consistingof cyclosporine, azathioprine, and methotrexate;

[0383] (11) anti-inflammatory glucocorticoids;

[0384] (12) penicillamine;

[0385] (13) hydroxychloroquine;

[0386] (14) anti-gout agents including colchicine; xanthine oxidaseinhibitors including allopurinol; and uricosuric agents selected fromprobenecid, sulfinpyrazone, and benzbromarone;

[0387] C. where older mammals are being treated for disease conditions,syndromes and symptoms found in geriatric mammals, said inhibitorycompound is administered in combination with one or more membersindependently selected from the group consisting essentially of:

[0388] (1) cognitive therapeutics to counteract memory loss andimpairment;

[0389] (2) anti-hypertensives and other cardiovascular drugs intended tooffset the consequences of atherosclerosis, hypertension, myocardialischemia, angina, congestive heart failure, and myocardial infarction,selected from the group consisting of:

[0390] a. diuretics;

[0391] b. vasodilators;

[0392] c. β-adrenergic receptor antagonists;

[0393] d. angiotensin II converting enzyme inhibitors (ACE-inhibitors),alone or optionally together with neutral endopeptidase inhibitors;

[0394] e. angiotensin II receptor antagonists;

[0395] f. renin inhibitors;

[0396] g. calcium channel blockers;

[0397] h. sympatholytic agents;

[0398] i. α₂-adrenergic agonists;

[0399] j. α-adrenergic receptor antagonists; and

[0400] k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics);

[0401] (3) antineoplastic agents selected from:

[0402] a. antimitotic drugs selected from:

[0403] i. vinca alkaloids selected from:

[0404] [1] vinblastine, and

[0405] [2] vincristine;

[0406] (4) growth hormone secretagogues;

[0407] (5) strong analgesics;

[0408] (6) local and systemic anesthetics; and

[0409] (7) H₂-receptor antagonists, proton pump inhibitors, and othergastroprotective agents.

[0410] The term “treating”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment, as used herein, refers tothe act of treating, as treating” is defined immediately above.

[0411] The term “livestock animals” as used herein refers todomesticated quadrupeds, which includes those being raised for meat andvarious byproducts, e.g., a bovine animal including cattle and othermembers of the genus Bos, a porcine animal including domestic swine andother members of the genus Sus, an ovine animal including sheep andother members of the genus Ovis, domestic goats and other members of thegenus Capra; domesticated quadrupeds being raised for specialized taskssuch as use as a beast of burden, e.g., an equine animal includingdomestic horses and other members of the family Equidae, genus Equus, orfor searching and sentinel duty, e.g., a canine animal includingdomestic dogs and other members of the genus Canis; and domesticatedquadrupeds being raised primarily for recreational purposes, e.g.,members of Equus and Canis, as well as a feline animal includingdomestic cats and other members of the family Felidae, genus Felis.

[0412] “Companion animals” as used herein refers to cats and dogs. Asused herein, the term “dog(s)” denotes any member of the species Canisfamiliaris, of which there are a large number of different breeds. Whilelaboratory determinations of biological activity may have been carriedout using a particular breed, it is contemplated that the inhibitorycompounds of the present invention will be found to be useful fortreating pain and inflammation in any of these numerous breeds. Dogsrepresent a particularly preferred class of patients in that they arewell known as being very susceptible to chronic inflammatory processessuch as osteoarthritis and degenerative joint disease, which in dogsoften results from a variety of developmental diseases, e.g., hipdysplasia and osteochondrosis, as well as from traumatic injuries tojoints. Conventional NSAID's, if used in canine therapy, have thepotential for serious adverse gastrointestinal reactions and otheradverse reactions including kidney and liver toxicity. Gastrointestinaleffects such as single or multiple ulcerations, including perforationand hemorrhage of the esophagus, stomach, duodenum or small and largeintestine, are usually debilitating, but can often be severe or evenfatal.

[0413] The term “treating reproductive disorders (preferably inlivestock animals)” as used herein refers to the use of the COX-2inhibitors of the invention in mammals, preferably livestock animals(cattle, pigs, sheep, goats or horses) during the estrus cycle tocontrol the time of onset of estrus by blocking the uterine signal forlysis of the corpus luteum, i.e. F-series prostaglandins, then removingthe inhibition when the onset of estrus is desired. There are settingswhere it is useful to control or synchronize the time of estrus,especially when artificial insemination or embryo transfer are to beperformed. Such use also includes enhancing the rate of embryo survivalin pregnant livestock animals. Blocking F-series prostaglandin releasecan have several beneficial actions including reducing uterinecontractions, enhancing uteroplacental bloodflow, supporting recognitionof pregnancy, and postponing lysis of the corpus luteum at the time whenestrus would have occurred had the animal not become pregnant (aroundDay 21 of pregnancy). Such treatment also abrogates the effects ofstress on reproduction. For example reductions in fertility caused byexcessive heat, negative energy balance and other stresses which have aCOX-2 mediated component, as does abortion induced by stress such asheat, transportation, co-mingling, palpation, infection, etc. Suchtreatment is also useful to control the time of parturition, which isaccompanied by release of F-series prostaglandins that lead to lysis ofthe corpus luteum. Inhibition of COX-2 would block the onset ofpremature labor in livestock animals, allowing the offspring time tomature before birth. Also there are settings where controlling the timeof parturition is a useful tool for management of pregnant animals.

[0414] The present invention also includes isotopically-labelledcompounds, which are identical to those recited in Formula i, but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ²¹P, ³²P, ³⁵S, ⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic and diagnostic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements and, hence, may be preferred in somecircumstances. Isotopically labelled compounds of Formula I of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

[0415] This invention also encompasses pharmaceutical compositionscontaining prodrugs of compounds of the formula I. This invention alsoencompasses methods of treating or preventing disorders that can betreated or prevented by the selective inhibition of COX-2 comprisingadministering prodrugs of compounds of the formula 1. Compounds offormula I having free amino, amido, hydroxy, carboxylic acid ester,sulfonamide or carboxylic groups (especially alkyl-NH—, aryl-NH—heteroaryl-NH—, heterocyclic-NH—, cycloalkyl-NH—, alkyl-S— andalkyl-(S═O)—) can be converted into prodrugs (such as alkyl-aryl-N—,aryl-heteroaryl-N—, aryl-heterocyclic-N—, aryl-cycloalkyl-N—, etc. (i.e.disubstitution of “N”)). Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues which are covalently joined through peptidebonds to free amino, hydroxy or carboxylic acid groups of compounds offormula I. The amino acid residues include the 20 naturally occurringamino acids commonly designated by three letter symbols and alsoinclude, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters are-covalently bonded to the above substituents offormula I through the carbonyl carbon prodrug sidechain. Prodrugs alsoinclude metabolically labile groups such as ethers, acetates, mercaptansand sulfoxides.

[0416] One of ordinary skill in the art will appreciate that thecompounds of the invention are useful in treating a diverse array ofdiseases. One of ordinary skill in the art will also appreciate thatwhen using the compounds of the invention in the treatment of a specificdisease that the compounds of the invention may be combined with variousexisting therapeutic agents used for that disease.

[0417] For the treatment of rheumatoid arthritis, the compounds of theinvention may be combined with agents such as TNF-α inhibitors such asanti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules(such as Enbrel®), low dose methotrexate, lefunimide,hydroxychloroquine, d-penicilamine, auranofin or parenteral or oralgold.

[0418] The compounds of the invention can also be used in combinationwith existing therapeutic agents for the treatment of osteoarthritis.Suitable agents to be used in combination include standard non-steroidalanti-inflammatory agents (hereinafter NSAID's) such as piroxicam,diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone,salicylates such as aspirin, COX-2 inhibitors such as celecoxib androfecoxib, analgesics and intraarticular therapies such ascorticosteroids and hyaluronic acids such as hyalgan and synvisc.

[0419] The active ingredient of the present invention may beadministered in combination with inhibitors of other mediators ofinflammation, comprising one or more members selected from the groupconsisting essentially of the classes of such inhibitors and examplesthereof which include, matrix metalloproteinase inhibitors, aggrecanaseinhibitors, TACE inhibitors, leucotriene receptor antagonists, IL-1processing and release inhibitors, IL-1 ra, H₁-receptor antagonists;kinin-B₁- and B₂-receptor antagonists; prostaglandin inhibitors such asPGD-, PGF- PGI₂—, and PGE-receptor antagonists; thromboxane A₂ (TXA2-)inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC₄-,LTD₄/LTE₄-, and LTB₄-inhibitors; PAF-receptor antagonists; gold in theform of an aurothio group together with various hydrophilic groups;immunosuppressive agents, e.g., cyclosporine, azathioprine, andmethotrexate; anti-inflammatory glucocorticoids; penicillamine;hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidaseinhibitors, e.g., allopurinol, and uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone.

[0420] The compounds of the present invention may also be used incombination with anticancer agents such as endosta tin and angiostatinor cytotoxic drugs such as adriamycin, daunomycin, cis-platinum,etoposide, taxol, taxotere and alkaloids, such as vincristine, andantimetabolites such as methotrexate.

[0421] The compounds of the present invention may also be used incombination with anti-hypertensives and other cardiovascular drugsintended to offset the consequences of atherosclerosis, includinghypertension, myocardial ischemia including angina, congestive heartfailure, and myocardial infarction, selected from vasodilators such ashydralazine, β-adrenergic receptor antagonists such as propranolol,calcium channel blockers such as nifedipine, α₂-adrenergic agonists suchas clonidine, α-adrenergic receptor antagonists such as prazosin, andHMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such aslovastatin or atorvastatin.

[0422] The active ingredient of the present invention may also beadministered in combination with one or more antibiotic, antifungal,antiprotozoal, antiviral or similar therapeutic agents.

[0423] The compounds of the present invention may also be used incombination with CNS agents such as antidepressants (such assertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex,MAOB inhibitors such as selegine and rasagiline, comP inhibitors such asTasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,nicotine agonists, dopamine agonists and inhibitors of neuronal nitricoxide synthase), 5-HTID agonists such as sumatriptan, elitriptan,rizatriptan and zolmitriptan and anti-Alzheimer's drugs such asdonepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.

[0424] The compounds of the present invention may also be used incombination with osteoporosis agents such as roloxifene, lasofoxifene,droloxifene or fosomax and immunosuppressant agents such as FK-506 andrapamycin.

[0425] The present invention also relates to the formulation of theactive agents of the present invention alone or with one or more othertherapeutic agents which are to form the intended combination, includingwherein said different drugs have varying half-lives, by creatingcontrolled-release forms of said drugs with different release timeswhich achieves relatively uniform dosing; or, in the case of non-humanpatients, a medicated feed dosage form in which said drugs used in thecombination are present together in admixture in said feed composition.There is further provided in accordance with the present inventionco-administration in which the combination of drugs is achieved by thesimultaneous administration of said drugs to be given in combination;including co-administration by means of different dosage forms androutes of administration; the use of combinations in accordance withdifferent but regular and continuous dosing schedules whereby desiredplasma levels of said drugs involved are maintained in the patient beingtreated, even though the individual drugs making up said combination arenot being administered to said patient simultaneously.

DETAILED DESCRIPTION OF THE INVENTION

[0426] Compounds of the formula I may be prepared according to thefollowing reaction schemes and discussion. Unless otherwise indicated,R¹ through R⁸, X, Y and A in the reaction schemes and discussion thatfollow are as defined above.

[0427] Scheme 1 illustrates a method of synthesizing compounds of theformula 1, wherein “A” is —O— and R³ is (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkylor (C₁-C₉)heterocyclic. Referring to Scheme 1, compounds of Formula Ican be prepared from the compounds of Formula II by reaction with acompound of the formula R³L, wherein L is a leaving group in thepresence of a base in a suitable solvent. Suitable leaving groupsinclude halides, such as chloride or bromide, or ester or esterequivalents. Examples of compounds of formula R³L include halo, ester orester equivalents (such as acylimidazole and dialkylamide), preferablyhalo ester and acylimidazole. Potassium iodide may also be added to thereaction mixture. Suitable bases include sodium hydride, potassiumcarbonate and triethylamine. Suitable solvents include DMSO, DMF, THF,dioxane, and acetonitrile. This reaction is generally carried out at atemperature from about 0° C. to about 140° C., preferably at about 50°C. to about 80° C. for a period from about 1 hour to about 24 hours.

[0428] The compounds of Formula II can be prepared from compounds ofFormula III by reaction with a compound of the formula

[0429] wherein R is (C₁-C₆)alkyl such as, 4,4,4-trifluoro-3-oxo-butyricacid methyl ester, in a suitable solvent under acidic, neutral or basicconditions. Suitable solvents include methanol, DMF, DMSO, water or amixture of them. Suitable acids include hydrochloric acid,trifluoroacetic acid. Suitable bases include sodium hydroxide, potassiumhydroxide, and potassium carbonate. This reaction is generally carriedout at a temperature from about 0° C. to about 140° C., preferably atabout 20° C. to about 100° C. for a period from about 1 hour to about 24hours.

[0430] Compounds of formula III are commercially available or can bemade by methods well known to those of ordinary skill in the art oraccording to Scheme 3. Compounds of formula III can be prepared by themethod described in Vavrina, et al, Collection Czechoslov. Chem.Commun., Vol. 37, 1721 (1972) and which are incorporated by reference.The regio isomeric pyrazole (Ia′) can be also prepared from thecorresponding 1,3-diketone and heteroarylhydrazine according to othermethods well known in the art.

[0431] Scheme 2 refers to an alternate preparation of compounds of theformula I. Referring to Scheme 2, compounds of the formula I areprepared from compounds of the formula IV, wherein L is a leaving groupsuch as a chloride or bromide, by reaction with a compound of theformula R³AH in the presence of a base and a polar solvent. Suitablebases include sodium hydride, potassium carbonate, and triethylamine.Suitable solvents include alcohols, such as ethanol, methanol, propanolor butanol; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),preferably an alcohol, most preferably ethanol. This reaction isgenerally carried out at a temperature from about 0° C. to about 140°C., preferably at about 20° C. to about 100° C. for a period from about1 hour to about 24 hours.

[0432] Compounds of the formula IV are prepared from compounds of theformula II by reaction with a halogenating reagent in a polar solvent.Suitable halogenating reagents include oxalyl chloride, POCl₃, POBr₃,SOCl₂ or PCl₅, preferably POCl₃. Suitable solvents includeN,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) orN-methyl-2-pyrrolidinone (NMP), preferably DMF. This reaction isgenerally carried out at a temperature from about 20° C. to about 140°C., preferably at about the reflux temperature of the polar solvent fora period from about 1 hour to about 48 hours.

[0433] Compounds of formula II are prepared according to the methods ofScheme 1.

[0434] Scheme 3 refers to the preparation of compounds of the formulaIII which are intermediates used in Scheme 1. Referring to Scheme 3,compounds of the formula III are prepared from compounds of the formulaV by reaction with hydrazine in the presence of a polar solvent.Suitable solvents include alcohols, such as ethanol, methanol, propanolor butanol; dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP),preferably an alcohol, most preferably ethanol. This reaction isgenerally carried out at a temperature from about 0° C. to about 140°C., preferably at about the reflux temperature of the polar solvent.Preferably the product is isolated as a salt, such as a hydrochoridesalt.

[0435] The compound of formula V is prepared from a compound of theformula VI by reaction with an oxidizing reagent in the presence of asolvent. Suitable oxidants include meta-chloroperbenzoic acid, hydrogenperoxide, sodium perborate, or Oxone® (Oxone® is preferred). Suitablesolvents or solvent mixtures include methanol-water, dioxane-water,tetrahydrofuran-water, methylene chloride, or chloroform, preferablymethanol-water. Suitable temperatures for the aforesaid reaction rangefrom about 0° C. to about 60° C., preferably the temperature may rangefrom about 20° C. to about 25° C. (i.e. room temperature). The reactionis complete within about 0.5 hours to about 24 hours, preferably about16 hours.

[0436] The compound of the formula VI is prepared from a compound offormula VI by reaction with a disulfide or methyl alkylthiolsulfonate ofthe formula R¹S-L, wherein L is alkylthio or methylsulfonate, in thepresence or absence of a base in a polar solvent. Suitable basesinclude, alkyllithium such as n-butyllithium, and suitable solventsinclude ether, benzene and THF. This reaction is generally carried outat a temperature from about −78° C. to 0° C. for from about 1 to 8hours.

[0437] Compounds of formula VII are commercially available or can bemade by methods well known to those of ordinary skill in the art.

[0438] Unless indicated otherwise, the pressure of each of the abovereactions is not critical. Generally, the reactions will be conducted ata pressure of about one to about three atmospheres, preferably atambient pressure (about one atmosphere).

[0439] The compounds of the formula I which are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate a compound of the formula Ifrom the reaction mixture as a pharmaceutically unacceptable salt andthen simply convert the latter back to the free base compound bytreatment with an alkaline reagent, and subsequently convert the freebase to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isobtained.

[0440] The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the base compounds of this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0441] Those compounds of the formula I which are also acidic in nature,eg., wherein R², R⁴, R⁵ or R⁶ include a —COOH, tetrazole or other acidicmoiety, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula I. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may, also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

Method for Assessing Biological Activities:

[0442] The activity of the compounds of the formula (I) of the presentinvention was demonstrated by the following assays.

[0443] Human In Vitro Assays

[0444] Human Cell-Based COX-1 assay

[0445] Human peripheral blood obtained from healthy volunteers wasdiluted to {fraction (1/10)} volume with 3.8% sodium citrate solution.The platelet-rich plasma immediately obtained was washed with 0.14 Msodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA.Platelets were then washed with platelet buffer (Hanks buffer (Ca free)containing 0.2% BSA and 20 mM Hepes). Finally, the human washedplatelets (HWP) were suspended in platelet buffer at the concentrationof 2.85×10⁸ cells/ml and stored at room temperature until use. The HWPsuspension (70 μl aliquots, final 2.0×10⁷ cells/ml) was placed in a96-well U bottom plate and 10 μl aliquots of 12.6 mM calcium chlorideadded. Platelets were incubated with A23187 (final 10 μM, Sigma) withtest compound (0.1-100 μM) dissolved in DMSO (final concentration; lessthan 0.01%) at 37° C. for 15 minutes. The reaction was stopped byaddition of EDTA (final 7.7 mM) and TxB2 in the supernatant quantitatedby using a radioimmunoassay kit (Amersham) according to themanufacturer's procedure.

[0446] Human Cell-Based COX-2 Assay

[0447] The human cell based COX-2 assay was carried out as previouslydescribed (Moore et al., Inflam. Res., 45, 54, 1996). Confluent humanumbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well flatbottom plate were washed with 80 ml of RPM11640 containing 2% FBS andincubated with hIL-1β (final concentration 300 U/ml, R & D Systems) at37° C. for 24 hr. After washing, the activated HUVECs were incubatedwith test compound (final concentration; 0.1 nM-1 μM) dissolved in DMSO(final concentration; less than 0.01.%) at 37° C. for 20 minutes andstimulated with A23187 (final concentration 30 mM) in Hanks buffercontaining 0.2% BSA, 20 mM Hepes at 37° C. for 15 minutes.6-Keto-PGF_(1α), stable metabolite of PGI2, in the supernatant wasquantitated by using a radioimmunoassay method (antibody; PreseptiveDiagnostics, SPA; Amersham).

[0448] Canine In Vitro Assays

[0449] The following canine cell based COX 1 and COX-2 assays have beenreported in Ricketts et al., Evaluation of Selective Inhibition ofCanine Cyclooxygenase 1 and 2 by Carprofen and Other NonsteroidalAnti-inflammatory Drugs, American Journal of Veterinary Research, 59(11), 1441-1446.

[0450] Protocol for Evaluation of Canine COX-1 Activity

[0451] Test drug compounds were solubilized and diluted the day beforethe assay was to be conducted with 0.1 mL of DMSO/9.9 mL of Hank'sbalanced salts solution (HBSS), and stored overnight at 4° C. On the daythat the assay was carried out, citrated blood was drawn from a donordog, centrifuged at 190×g for 25 minutes at room temperature, and theresulting platelet-rich plasma was then transferred to a new tube forfurther procedures. The platelets were washed by centrifuging at 1500×gfor 10 minutes at room temperature. The platelets were washed withplatelet buffer comprising Hank's buffer (Ca free) with 0.2% bovineserum albumin (BSA) and 20 mM HEPES. The platelet samples were thenadjusted to 1.5×10⁷/mL, after which 50 μl of calcium ionophore (A23187)together with a calcium chloride solution were added to 50 μl of testdrug compound dilution in plates to produce final concentrations of 1.7μM A23187 and 1.26 mM Ca. Then, 100 μl of canine washed platelets wereadded and the samples were incubated at 37° C. for 15 minutes afterwhich the reaction was stopped by adding 20 μl of 77 mM EDTA. The plateswere then centrifuged at 2000×9 for 10 minutes at 4° C., after which 50μl of supernatant was assayed for thromboxane B₂ (TXB₂) byenzyme-immunoassay (EIA). The pg/mL of TXB₂ was calculated from thestandard line included on each plate, from which it was possible tocalculate the percent inhibition of COX-1 and the IC₅₀ values for thetest drug compounds.

[0452] Protocol for Evaluation of Canine COX-2 Activity

[0453] A canine histiocytoma (macrophage-like) cell line from theAmerican Type Culture Collection designated as DH82, was used in settingup the protocol for evaluating the COX-2 inhibition activity of varioustest drug compounds. There was added to flasks of these cells 10 μg/mLof LPS, after which the flask cultures were incubated overnight. Thesame test drug compound dilutions as described above for the COX-1protocol were used for the COX-2 assay and were prepared the day beforethe assay was carried out. The cells were harvested from the cultureflasks by scraping, and were then washed with minimal Eagle's media(MEM) combined with 1% fetal bovine serum, centrifuged at 1500 rpm for 2minutes, and adjusted to a concentration of 3.2×10⁵ cells/mL. To 50 μlof test drug dilution there was added 50 μl of arachidonic acid in MEMto give a 10 μM final concentration, and there was added as well 100 μlof cell suspension to give a final concentration of 1.6×10⁵ cells/mL.The test sample suspensions were incubated for 1 hour and thencentrifuged at 1000 rpm for 10 minutes at 4° C., after which 50 μlaliquots of each test drug sample were delivered to EIA plates. The EIAwas performed for prostaglandin E₂ (PGE₂), and the pg/mL concentrationof PGE₂ was calculated from the standard line included on each plate.From this data it was possible to calculate the percent inhibition ofCOX-2 and the IC₅₀ values for the test drug compounds. Repeatedinvestigations of COX-1 and COX-2 inhibition were conducted over thecourse of several months. The results are averaged, and a singleCOX-1:COX-2 ratio is calculated.

[0454] Whole blood assays for COX-1 and COX-2 are known in the art suchas the methods described in C. Brideau, et al., A Human Whole BloodAssay for Clinical Evaluation of Biochemical Efficacy of CyclooxygenaseInhibitors, Inflammation Research, Vol. 45, pp. 68-74 (1996). Thesemethods may be applied with feline, canine or human blood as needed.

[0455] In Vivo Assays

[0456] Carrageenan Induced Foot Edema in Rats

[0457] Male Sprague-Dawley rats (5 weeks old, Charles River Japan) werefasted overnight. A line was drawn using a marker above the ankle on theright hind paw and the paw volume (V0) was measured by waterdisplacement using a plethysmometer (Muromachi). Animals were givenorally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a testcompound (2.5 ml per 100 g body weight). One hour later, the animalswere then injected intradermally with X-carrageenan (0.1 ml of 1% w/vsuspension in saline, Zushikagaku) into right hind paw (Winter et al.,Proc. Soc. Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim.Forsch., 25, 1629, 1975) and three hours later, the paw volume (V3) wasmeasured and the increase in volume (V3-V0) calculated. Since maximuminhibition attainable with classical NSAID's is 60-70%, ED30 values werecalculated.

[0458] Gastric Ulceration in Rats

[0459] The gastric ulcerogenicity of test compound was assessed by amodification of the conventional method (Ezer et al., J. Pharm.Pharmacol., 28, 655, 1976; Cashin et al.; J. Pharm. Pharmacol., 29,330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles RiverJapan), fasted overnight, were given orally either vehicle (0.1% methylcellulose or 5% Tween 80) or a test compound (1 ml per 10 g bodyweight). Six hours after, the animals were sacrificed by cervicaldislocation. The stomachs were removed and inflated with 1% formalinsolution (10 ml). Stomachs were opened by cutting along the greatercurvature. From the number of rats that showed at least one gastriculcer or hemorrhaging erosion (including ecchymosis), the incidence ofulceration was calculated. Animals did not have access to either food orwater during the experiment.

[0460] Canine Whole Blood Ex Vivo Determinations of COX-1 and COX-2Activity Inhibition

[0461] The in vivo inhibitory potency of a test compound against COX-1and COX-2 activity may be evaluated using an ex vivo procedure on caninewhole blood. Three dogs were dosed with 5 mg/kg of the test compoundadministered by oral gavage in 0.5% methylcellulose vehicle and threedogs were untreated. A zero-hour blood sample was collected from alldogs in the study prior to dosing, followed by 2- and 8-hour post-doseblood sample collections. Test tubes were prepared containing 2 μL ofeither (A) calcium ionophore A23187 giving a 50 μM final concentration,which stimulates the production of thromboxane B₂ (TXB₂) for COX-1activity determination; or of (B) lipopolysaccharide (LPS) to give a 10μg/mL final concentration, which stimulates the production ofprostaglandin E₂ (PGE₂) for COX-2 activity determination. Test tubeswith unstimulated vehicle were used as controls. A 500 μL sample ofblood was added to each of the above-described test tubes, after whichthey were incubated at 37° C. for one hour in the case of the calciumionophore-containing test tubes, and overnight in the case of theLPS-containing test tubes. After incubation, 10 μL of EDTA was added togive a final concentration of 0.3%, in order to prevent coagulation ofthe plasma which sometimes occurs after thawing frozen plasma samples.The incubated samples were centrifuged at 4° C. and the resulting plasmasample of 200 μL was collected and stored at −20° C. in polypropylene96-well plates. In order to determine endpoints for this study, enzymeimmunoassay (EIA) kits available from Cayman were used to measureproduction of TXB₂ and PGE₂, utilizing the principle of competitivebinding of tracer to antibody and endpoint determination by colorimetry.Plasma samples were diluted to approximate the range of standard amountswhich would be supplied in a diagnostic or research tools kit, i.e.,{fraction (1/500)} for TXB₂ and {fraction (1/750)} for PGE₂.

[0462] Data Analysis

[0463] Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView(Abacus Cencepts, Inc.) for Macintosh were used. Differences betweentest compound treated group and control group were tested for usingANOVA. The IC₅₀ (ED₃₀) values were calculated from the equation for thelog-linear regression line of concentration (dose) versus percentinhibition.

[0464] Most compounds prepared in the Working Examples as describedhereinafter were tested by at least one of the methods described above,and showed IC₅₀ values of 0.001 μM to 3 μM with respect to inhibition ofCOX-2 in either the canine or human assays.

[0465] COX-2 selectivity can be determined by ratio in terms of IC₅₀value of COX-1 inhibition to COX-2 inhibition. In general, it can besaid that a compound showing a COX-2/COX-1 inhibition ratio of more than5 has good COX-2 selectivity.

[0466] The compounds of the formula (I) of this invention can beadministered via oral, parenteral, anal, buccal or topical routes tomammals (including humans, dogs, cats, horses and livestock animals).

[0467] In general, these compounds are most desirably administered tohumans in doses ranging from 0.01 mg to 100 mg per kg of body weight perday, although variations will necessarily occur depending upon theweight, sex and condition of the subject being treated, the diseasestate being treated and the particular route of administration chosen.However, a dosage level that is in the range of from 0.1 mg to 10 mg perkg of body weight per day, single or divided dosage is most desirablyemployed in humans for the treatment of above-mentioned diseases.

[0468] These compounds are most desirably administered to said non-humanmammals, e.g. dogs, cats, horses or livestock animals in an amount,expressed as mg per kg of body weight of said member per day, rangingfrom about 0.01 mg/kg to about 20.0 mg/kg/day, preferably from about 0.1mg/kg to about 12.0 mg/kg/day, more preferably from about 0.5 mg/kg toabout 10.0 mg/kg/day, and most preferably from about 0.5 mg/kg to about8.0 mg/kg/day.

[0469] The compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby any of the above routes previously indicated, and such administrationcan be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, trochees, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically-effective compounds of this inventionare present in such dosage forms at concentration levels ranging 5% to70% by weight, preferably 10% to 50% by weight.

[0470] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

[0471] A preferred composition for dogs comprises an ingestible liquidperoral dosage form selected from the group consisting of a solution,suspension, emulsion, inverse emulsion, elixir, extract, tincture, andconcentrate, optionally to be added to the drinking water of the dogbeing treated. Any of these liquid dosage forms, when formulated inaccordance with methods well known in the art, can either beadministered directly to the dog being treated, or may be added to thedrinking water of the dog being treated. The concentrate liquid form, onthe other hand, is formulated to be added first to a given amount ofwater, from which an aliquot amount may be withdrawn for administrationdirectly to the dog or addition to the drinking water of the dog.

[0472] A preferred composition provides delayed-, sustained-, and/orcontrolled-release of said anti-inflammatory selective COX-2 inhibitor.Such preferred compositions include all such dosage forms whichproduce >80% inhibition of COX-2 isozyme activity and result in a plasmaconcentration of said inhibitor of at least 3 fold the COX-2 IC₅₀ for atleast 4 hours; preferably for at least 8 hours; more preferably for atleast 12 hours; more preferably still for at least 16 hours; even morepreferably still for at least 20 hours; and most preferably for at least24 hours. Preferably, there is included within the above-describeddosage forms those which produce ≧80% inhibition of COX-2 isozymeactivity and result in a plasma concentration of said inhibitor of atleast 5 fold the COX-2 IC₅₀ for at least 4 hours, preferably for atleast 8 hours, more preferably for at least 12 hours, still morepreferably for at least 20 hours, and most preferably for at least 24hours. More preferably, there is included the above-described dosageforms which produce ≧90% inhibition of COX-2 isozyme activity and resultin a plasma concentration of said inhibitor of at least 5 fold the COX-2IC₅₀ for at least 4 hours, preferably for at least 8 hours, morepreferably for at least 12 hours, still more preferably for at least 20hours, and most preferably for at least 24 hours.

[0473] For parenteral administration, solutions of a compound of thepresent invention in either sesame or peanut oil or in aqueous propyleneglycol may be employed. The aqueous solutions should be suitablybuffered (preferably pH>8) if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

[0474] The compounds of formula (I) may also be administered in the formof suppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

[0475] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0476] For transdermal administration, transdermal patches prepared inaccordance with well known drug delivery technology may be prepared andapplied to the skin of a mammal, preferably a human or a dog, to betreated, whereafter the active agent by reason of its formulatedsolubility characteristics migrates across the epidermis and into thedermal layers of the skin where it is taken up as part of the generalcirculation, ultimately providing systemic distribution of the activeingredient over a desired, extended period of time. Also included areimplants which are placed beneath the epidermal layer of the skin, i.e.between the epidermis and the dermis of the skin of the patient beingtreated. Such an implant will be formulated in accordance with wellknown principles and materials commonly used in this deliverytechnology, and may be prepared in such a way as to provide controlled-,sustained-, and/or delayed-release of the active ingredient into thesystemic circulation of the patient. Such subepidermal (subcuticular)implants provide the same facility of installation and deliveryefficiency as transdermal patches, but without the limitation of beingsubject to degradation, damage or accidental removal as a consequence ofbeing exposed on the top layer of the patient's skin.

EXAMPLES

[0477] The following examples contain detailed descriptions of themethods of the preparation of compounds of formula (I). These detaileddescriptions fall within the scope of the invention and serve toexemplify the above described general synthetic procedures which formpart of the invention. These detailed descriptions are presented forillustrative purposes only and are not intended to restrict the scope ofthe present invention.

[0478] The invention is illustrated in the following non-limitingexamples in which, unless stated otherwise: all operations were carriedout at room or ambient temperature, that is, in the range of 18-25° C.;evaporation of solvent was carried out using a rotary evaporator underreduced pressure with a bath of up to 60° C.; reactions were monitoredby thin layer chromatography (tic) and reaction times are given forillustration only; melting points (m.p.) given are uncorrected(polymorphism may result in different melting points); structure andpurity of all isolated compounds were assured by at least one of thefollowing techniques: tic (Merck silica gel 60 F-254 precoated plates),mass spectrometry, nuclear magnetic resonance (NMR) or infraredspectroscopy (IR). IR data were obtained on a FTIR 8200 (SHIMAZUSpectrometer). Yields are given for illustrative purposes only. Flashcolumn chromatography was carried out using Merck silica gel 60 (230-400mesh ASTM). Low-resolution mass spectral data (EI) were obtained on aAutomass 120 (JEOL) mass spectrometer. Liquid Chromatography data wascollected on a Hewlett Packard 1100 Liquid Chromatography/Mass SelectiveDetector (LC/MSD). Analysis was performed on a Luna C-18 column withdimensions of 3.0×150 mm. The flow rate was 0.425 ml/minute running agradient of 50% 0.1% aqueous formic acid and 50% acetonitrile to 100%acetonitrile in 15 minutes. The ionization type for the mass detector ofthe Mass Spectrophotometer was atmospheric pressure electrospray in thepositive ion mode with a fragmentor voltage of 50 volts. NMR data wasdetermined at 270 MHz (JEOL JNM-LA 270 spectrometer) using deuteratedchloroform (99.8% D), methanol (99.8% D) or dimethylsulfoxide (99.9% D)as solvent unless indicated otherwise, relative to tetramethylsilane(TMS) as internal standard in parts per million (ppm); conventionalabbreviations used are: s=singlet, d=doublet, t triplet, q=quartet,m=multiplet, br=broad, etc.

[0479] The following abbreviations are used: THF: tetrahydrofuranCH₂Cl₂: dichloromethane NaHCO₃: sodium bicarbonate HCl: hydrogenchloride MgSO₄: magnesium sulfate Na₂SO₄: sodium sulfate DME:dimethoxyethane n-BuLi: n-butyllithium DMF: dimethylformamide

EXAMPLE 1

[0480]2-(5-ISOPROPOXY-3-TRIFLUOROMETHYL-PYRAZOL-1-YL)-5-METHANESULFONYL-PYRIDINE

[0481]2-(5-Methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-ol(616 mg) was dissolved in dimethyl formamide (DMF) (7.5 ml), followed bythe addition of potassium carbonate (K₂CO₃) (1.1 g) and isopropyl iodide(510 mg). The reaction mixture was then stirred at 75° C. for 1.5 hours.After cooling to room temperature, the reaction mixture was then dilutedwith 50 ml of 2:1 ethylacetate:benzene solution. The organic layer waswashed with 0.5 N sodium hydroxide solution (50 ml), dried with sodiumsulfate, and the solvent was evaporated in vacuo to give the crudeproduct which was purified by recrystallization from 10 ml of 2:1isooctane:dichloromethane to yield the title compound (308 mg).

[0482] The compounds of Table 1 were prepared according to the method ofExample 1, substituting the appropriate alkyl or cycloalkyl halide.

[0483] The compounds of Examples 3-13 and 17-24 were prepared using thealkyl or cycloalkyl iodide, and the reaction time is between 1.5 hoursto about 24 hours.

[0484] The compounds of Examples 14-16 and 26-31 were prepared using thealkyl or cycloalkyl bromide or chloride. When alkyl bromide or alkylchloride was used, 2 equivalents of potassium iodide were also added tothe reaction mixture. TABLE 1 Example Formula LC MS 2

6.494 350 3

9.73 390.1 4

4.318 322 5

5.454 336 6

7.064 350 7

8.486 364 8

10.034 378.1 9

8.504 364.1 10

7.89 364 11

9.151 378.1 12

8.456 376.1 13

6.249 348 14

7.047 362 15

7.439 362.1 16

9.011 376 17

9.753 432 18

8.483 416.1 19

10.036 466.1 20

8.369 398.1 21

4.576 399.1 22

2.525 399.1 23

8.563 399.1 24

10.404 448.1 25

7.675 449.1 26

9.528 412.1 27

9.756 432 28

9.474 412.1 29

8.472 416 30

9.897 432 31

8.846 428.1

EXAMPLE 32

[0485]2-FLUORO-4-(5-ISOPROPOXY-3-TRIFLUOROMETHYL-PYRAZOL-1-YL)-BENZENESULFONAMIDE

[0486]2-Fluoro-4-(5-hydroxy-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonamide(163 mg) and potassium carbonate (276 mg) were mixed in dimethylformamide, followed by the addition of isopropyl iodide. The reactionmixture was stirred at 50° C. for 1.5 hours. After cooling to roomtemperature, 0.5 N sodium hydroxide solution (10 ml) was added, and theproduct was extracted with ethyl acetate (50 ml) and benzene (25 ml).The organic layer was dried with sodium sulfate, and the solvent wasevaporated in vacuo to give the crude product, which was purified bypreparative silica gel plate using 5:2 of hexane:ethyl acetate to affordthe title compound (32 mg). The title compound was characterized bytandem high pressure liquid chromatography/mass spectrometry and yieldeda retention time of 7.523 minutes and had a parent ion at 368 AMU.

[0487] The compounds of Table 2 were prepared according to methodsanalogous to Example 32 substituting the appropriate pyrazole andhalide. TABLE 2 EX STRUCTURE LC MS 33

9.096 382.1 34

9.249 394.1 35

10.334 408.1 36

6.316 348.0 37

8.063 398.1

EXAMPLE 38

[0488]2-(5-ISOPROPOXY-4-CHLORO-3-TRIFLUOROMETHYL-PYRAZOL-1-YL)-5-METHANESULFONYL-PYRIDINE

[0489]2-(5-Isopropoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine(105 mg) and NCS(N-chlorosuccinimide) (200 mg) were dissolved in DMFunder nitrogen, and the reaction mixture was stirred at room temperaturefor 2.5 days. The reaction mixture was then diluted with 2:1 ethylacetate:benzene solution (100 ml), and washed with 0.5 N sodiumhydroxide solution (100 ml), water (100 ml), and brine (100 ml). Theorganic layer was dried with sodium sulfate, and the solvent wasevaporated in vacuo to give the crude product which was purified byrecrystallization from 2:1 of isooctane:methylene chloride to afford thetitle compound (13 mg, 11%, MS: 384.1).

EXAMPLE 39

[0490]5-ISOPROPYLAMINO-1-(5-METHANESULFONYL-PYRIDIN-2-YL)-3-TRIFLUOROMETHYL-1H-PYRAZOLE-4-CARBALDEHYDE

[0491] To a solution of the chloro aldehyde pyrazole (40 mg, 0.113 mmol)in dry dichloromethane (1 ml) was treated sequentially with theisopropyl amine (11 ul, 1.1 equiv) and triethyl amine (19 ul, 1.2 equiv)and stirred vigorously at room temperature for 2 hours. The reactionmixture was taken up in water (15 ml) and extracted with dichloromethane(10 ml×3), dried, and concentrated in vacuo to give crude product.Purification by flash chromatography gave 6 mg (14%) of product as palewhite solid.

[0492] Liquid Chromatography/Mass Spectral Detection, as defined above,were 8.12 minutes and 377 AMU respectively.

EXAMPLE 40

[0493]1-(5-METHANESULFONYL-PYRIDIN-2-YL)-5-PHENYLSULFANYL-3-TRIFLUOROMETHYL-1H-PYRAZOLE-4-CARBALDEHYDE

[0494] To a solution of the chloro aldehyde pyrazole (40 mg, 0.113 mmol)in dry dichloromethane (1 ml) was treated sequentially with thethiophenol (13 μl, 1.1 equiv) and triethyl amine (19 μl, 1.2 equiv) andstirred vigorously at room temperature for 2 hours. The reaction mixturewas taken up in water (15 ml) and extracted with dichloromethane (10ml×3), dried, and concentrated in vacuo to give 47 mg (98%) of theproduct as a pale white solid. Structure confirmed by LCMS (RetentionTime 8.32 minutes, Parent Ion 428).

[0495] The compounds of Table 3 were prepared according to the methodsof Examples 39-40 substituting the appropriate pyrazole, thiol andamine. TABLE 3 EXAMPLE MOLSTRUCTURE MS (M + H) RT 41

377 8.12 42

394 8.01 43

434 10.63 44

428 2.5 45

388 2.8 46

402 3.5 47

417

EXAMPLE 48

[0496][5-CYCLOPENTYLAMINO-1-(5-METHANESULFONYL-PYRIDIN-2-YL)-3-TRIFLUOROMETHYL-1H-PYRAZOL-4-YL]-METHANOL

[0497] A solution of the aldehyde (Example 46) (50 mg) in dry methanol(3 ml) was cooled to 0° C. and treated with sodium borohydride (1.2equiv). The reaction mixture was allowed to warm to room temperature andstirred for 45 minutes. The reaction mixture was poured into 1 N HCl (10ml) and extracted with ethyl acetate (3×15 ml), dried and concentratedin vacuo. The crude product was purified by preparative TLC (2%methanol/methylene chloride) to provide 30 mg (60%) of the desiredproduct as a white solid.

[0498] Liquid Chromatography/Mass Spectral Detection, as defined above,were 6.98 minutes and 405 AMU respectively.

EXAMPLE 49

[0499]5-CYCLOPENTYLAMINO-1-(5-METHANESULFONYL-PYRIDIN-2-YL)-3-TRIFLUOROMETHYL-1H-PYRAZOLE-4-CARBONITRILE

[0500] A solution of the aldehyde (Example 46) (50 mg) in dry methanol(3 ml) was treated with phenyloxyamine (1.2 equiv) and the resultingmixture heated at 50° C. for 2 hours. The reaction mixture was dilutedwith water and extracted with ethyl acetate, (3×15 ml), dried andconcentrated to provide the intermediate oxime. This intermediate wasimmediately taken up in tetrahydrofuran and treated with sodium hydride(about 2 equivalents) and heated to 50° C. After completion of reactionby thin layer chromatography (TLC), the crude mixture was taken up inwater and extracted with ethyl acetate, dried and concentrated to givecrude product. Purification with preparative TLC (2% methanol:methylenechloride) gave 4 mg (8%) the desired nitrile as a white solid.

[0501] Liquid Chromatography/Mass Spectral Detection, as defined above,were 10.36 minutes and 400.1 AMU respectively.

EXAMPLE 50

[0502]5-CYCLOPENTYLAMINO-1-(5-METHANESULFONYL-PYRIDIN-2-YL)-3-TRIFLUOROMETHYL-1H-PYRAZOLE-4-CARBALDEHYDEO-METHYL-OXIME

[0503] A solution of the aldehyde (Example 46) (20 mg) in drydichloroethane (2 ml) was treated with methoxyamine (5.7 ul, 1.5 equiv)and the reaction mixture stirred at 80° C. for 7 hours. The reactionmixture was poured into water (15 ml) and extracted with ethyl acetate(3×15 ml), dried and concentrated in vacuo. The crude mixture waspurified by preparative TLC (35% EtOAc/Hexane) to provide 8 mg (36%) ofproduct as a white solid.

[0504] Liquid Chromatography/Mass Spectral Detection, as defined above,were 12.8 minutes and 432 AMU respectively. The compounds of Table 4were prepared according to the methods of Examples 39, 40 and 48-50substituting the appropriate pyrazole, thiol and amine. TABLE 4 EXAMPLEMOLSTRUCTURE MS (M + H) RT 51

432 12.1 52

389 8.09 53

431 NT 54

407 7.71 55

417 11.2 56

426 4.54 57

405 10.7 58

425 9.07 59

389 8.49 60

439 8.88 61

428 12.8

Preparation 1

[0505] Preparation of 3-PYRIDYL HYDRAZINES

[0506] Step 1: 3-NITRO-6-(METHYLTHIO)PYRIDINE

[0507] 2-Mercapto-5-nitro pyridine (20.0 g, 128 mmol) was suspended inwater/ethanol (43 mL/13 mL). Sodium carbonate monohydrate (17.49 g, 141mmol, dissolved in 86 mL of water) was added to the above slurrydropwise. Methyl iodide (20.0 g, 141 mmol) was added to the abovemixture and the mixture was stirred at room temperature for one hour.The solid was filtered and washed with water and ethanol to provide thetitle compound in quantitative yield.

[0508] Step 2: 3-NITRO-6-(METHYLSULFONYL)PYRIDINE

[0509] 3-Nitro-6-(methylthio)pyridine (22.0 g, 129.3 mmol) was dissolvedin acetone (140 mL). Sulfuric acid (2N, 230 mL) was then added dropwiseto above solution to form a slurry. Potassium permanganate (KMnO₄) (26.5g, 168.1 mmol, dissolved in 500 mL of H₂O) was added to the abovemixture dropwise. The mixture that resulted was stirred at roomtemperature overnight. The solid was filtered and stirred with a warmmixture of ethanol/methanol (10/1). The insoluble salt was filtered, thefiltrate was concentrated to provide a pale yellow solid. The crudeproduct was recrystallized from ethanol to furnish the title compound(17.8 g, 70%).

[0510] Step 3: 3-AMINO-6-(METHYLSULFONYL)PYRIDINE

[0511] 3-Nitro-6-(methylsulfonyl)pyridine (10 g, 49.5 mmol) wassuspended in water (200 mL). Iron powder (5.0 g, 89.3 mmol) and aceticacid (0.5 mL) were added to the above mixture. The mixture, whichresulted, was heated to reflux for 2 hours. The reaction was monitoredby thin layer chromatography (ethyl acetate/hexane, 1/1). The reactionmixture was then cooled to room temperature and a saturated solution ofsodium bicarbonate (NaHCO₃) (100 mL) was added to the mixture. Ethylacetate (200 mL) was added to the above mixture and the mixture, whichresulted, was stirred at room temperature for 30 minutes. The mixturewas filtered through Celite® and the organic layer was collected. Theaqueous layer was extracted with ethyl acetate (200 mL×3). The organicextractions were combined and dried over sodium sulfate. The solvent wasremoved under reduced pressure to provide the3-amino-6-(methylsulfonyl)pyridine (6 g, 70.5%).

[0512] Step 4: 5-HYDRAZINO-2-(METHYLSULFONYL)PYRIDINE

[0513] To a solution of 3-amino-6-(methylsulfonyl)pyridine (3.72 g, 21.6mmol) in concentrated hydrochloric acid (30 mL), sodium nitrite (1.78 g,25.7 mmol) in water (20 mL) was added dropwise at −10° C. to −15° C. andthe mixture was stirred for 2 hours at −10° C. to −5° C. (Note: thereaction was monitored by thin layer chromatography to make sure all thestarting material was consumed). Tin(II) chloride dihydrate (20 g, 88.6mmol) in concentrated hydrochloric acid (30 mL) was added dropwise at−5° C. The mixture was stirred 1 hour at −5° C. and then left overnight.The mixture was basified with aqueous sodium hydroxide (pH=9) with icecooling and tetrahydrofuran (200 mL) was added and stirred for 30minutes. The mixture was filtered by Celite® and the filtrate wasextracted with tetrahydrofuran (200 mL×3). The organic extraction wascombined and dried over magnesium sulfate and concentrated under reducedpressure to provide the title compound (3.2 g, 78.8%).

[0514] 5-Hydrazino-2-(methylsulfonyl)pyridine was dissolved inHCl-methanol (10%, 30 mL) and volatiles were removed under reducedpressure. The residue was washed with ether and employed directly tonext step without further purification.

[0515]¹H-NMR (DMSO-d₆) δ: 8.40-8.37 (m, 1H), 7.96 (d, J=8.6 Hz, 1H),7.55-7.45 (m, 1H), 3.19 (s, 3H).

Preparation 2

[0516] Preparation of 2-PYRIDYL HYDRAZINES

[0517] 2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride

[0518] 5-Methylthio-2-bromopyridine. (step 1)

[0519] To a solution of 2,5-dibromopyridine (23.4 g, 0.099 mol) in ether(500 mL), n-butyl lithium (1.52 M in n-hexane, 68 mL, 0.10 mmol) wasadded dropwise at −78° C. and the mixture was stirred for 1 hour at thetemperature. Dimethyldisulfide (9.8 mL, 0.11 mol) was added slowly at−78° C. and the mixture was stirred for 1 hour at that temperature andfurther 1 hour at 0° C. The mixture was quenched with aqueous 1Nhydrochloric acid (200 mL) and extracted with ether (100 mL×2), driedover magnesium sulfate (MgSO₄), and concentrated in vacuo gave the titlecompound (18.9 g, 94%).

[0520]¹H-NMR (CDCl₃) δ: 8.24 (dd, J=0.8, 2.5 Hz, 1H), 7.43 (dd, J=2.8,8.4 Hz, 1H), 7.38 (dd, J=0.8, 8.4 Hz, 1H), 2.50 (s, 3H).

[0521] 5-Methylsulfonyl-2-bromopyridine. (step 2)

[0522] To a solution of 5-methylthio-2-bromopyridine from step 1 (18.9g, 0.093 mol) in methylene chloride (600 mL), m-chloroperbenzoic acid(48 g, 0.19 mol) was added portionwise at 0° C. and the mixture wasstirred for 2 hours at room temperature. Aqueous saturated Na₂SO₃ (200mL) was added and stirred for 15 minutes and organic phase was separatedand washed with aqueous saturated sodium bicarbonate (NaHCO₃) (200 mL),dried over magnesium sulfate (MgSO₄), and concentrated in vacuo gave thetitle compound (20.9 g, 96%).

[0523]¹H-NMR (CDCl₃) δ: 8.91 (d, J=2.6 Hz, 1H), 8.06 (dd, J=2.6, 8.4 Hz,1H), 7.73 (d, J=8.4 Hz, 1H), 3.12 (s, 3H).

[0524] 2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride. (step3)

[0525] A mixture of 5-methylsulfonyl-2-bromopyridine from step 2 (20.9g, 0.088 mol) and anhydrous hydrazine (5.6 mL, 0.18 mol) in ethanol (200mL) was refluxed for 4 hours. After cooled to room temperature themixture was concentrated. The residual solid was washed with aqueoussaturated NaHCO₃ (100 mL) and water (100 mL) and collected by filtrationto give pale yellow solid (9.6 g). The solid was treated with 10%methanolic HCl (80 mL) and the precipitate was collected by filtrationto give the title compound (9.8 g, 50%).

[0526] H-NMR (DMSO-d₆) δ: 8.54 (s, 1H), 7.99 (d, J=8.9 Hz, 1H), 6.94 (d,J=8.9 Hz, 1H), 3.20 (s, 3H). (hydrazine proton was not detected).

Preparation 3

[0527] 2-FLUORO-4-HYDRAZINO-BENZENESULFONAMIDE

[0528] N-(3-Fluoro-4-sulfamoyl-phenyl)-acetamide (Step 1)

[0529] Chlorosulfonic acid (200 ml, 3 mol) was added in a 3-necked 1liter flask, followed by the portionwise addition ofN-(3-fluoro-phenyl)-acetamide (91.8 g, 600 mmol) in an ice-water bath.The reaction mixture was then heated at 70° C. for 5 hours, and thencooled down to room temperature. The reaction mixture was diluted withmethylene chloride (300 ml), and the resulting mixture was poured into 1liter of crushed ice. The aqueous layer was extracted with methylenechloride (2×400 ml), and the combined organic layers were concentratedto about 300 ml in vacuo. The residue was cooled in an ice-water bath,and 28% ammonia (120 ml) was slowly added over 1 hour, and thetemperature in the reaction flask was maintained between 0° C. to 10° C.The white precipitate was formed, and it was collected by filtrationdrying under high vacuum (71.0 g, 51%).

[0530] 4-Amino-2-fluoro-benzenesulfonamide (Step 2)

[0531] To a stirred solution of sodium hydroxide (120 g, 3 mol) in water(500 ml) was added N-(3-Fluoro-4-sulfamoyl-phenyl)-acetamide (69.7 g,300 mmol). The reaction mixture was stirred at reflux temperature for 3hours. The solution was then cooled to room temperature, and the pH wasadjusted to 6 by addition of 5N HCl solution. Most of the solvent wasremoved in vacuo, and the product precipitated out. The product wascollected by filtration and drying under vacuum at 60° C. (32 g, 56%).

[0532] 2-Fluoro-4-hydrazino-benzenesulfonamide Hydrochloride Salt (Step3)

[0533] To a stirred suspension of 4-Amino-2-fluoro-benzenesulfonamide(15.2 g, 80 mmol) in concentrated hydrochloric acid solution (180 ml)was slowly added NaNO₂ (5.8 g, 84 mmol) in water (180 ml), whilemaintaining the internal temperature between −15° C. and −20° C. in adry ice/acetonitrile bath. After the reaction mixture was stirred at−20° C. for 30 minutes, a solution of tin chloride (SnCl₂) hydrate (90.3g, 400 mmol) in concentrated hydrochloric acid solution (100 ml) wasadded dropwise, and the reaction mixture temperature was maintainedbetween −5° C. and −10° C. with an ice/methanol bath. The stirring wascontinued at −10° C. for 1 hour and then at room temperature for 4hours. The pH of the solution was adjusted to 8 by addition of 5 N NaOHsolution at 0° C., and the precipitate was removed by filtration throughcelite. The aqueous layer was extracted with tetrahydrofuran (3×600 ml),and the combined organic layers were washed with brine, dried overmagnesium sulfate (MgSO₄), and concentrated in vacuo. The residue wasdissolved in 10% methanolic HCl solution, followed by stirring at roomtemperature for 1 hour. The title compound was collected by filtration(12.5 g, 65%).

Preparation 4

[0534] 2-SULFAMYL-5-HYDRAZINO-PYRIDINE HYDROCHLORIDE SALT

[0535] 2-Sulfamyl-5-amino-pyridine (Step 1)

[0536] N-(6-Mercapto-pyridin-3-yl)-acetamide (30 g, 17.3 mmol) wasdissolved in cold concentrated hydrochloric acid solution (225 ml),followed by the addition of ice water (50 ml). Chlorine was bubbled intosolution, and the temperature was kept below 10° C. The solution becamedark brown first, and the chlorination was complete after 3 hours whenthe temperature no longer rose and the color of the solution lightened.The reaction was diluted with ice and water (1.2 kg) while keeping thetemperature below 10° C. The product, 5-acetylamino-pyridine-2-sulfonylchloride, was collected by filtration and air-dried. This was thensuspended in chloroform (CHCl₃) (200 mL), followed by the addition of30% ammonia solution (100 ml), and the resulting reaction mixture wasstirred for 2 hours. The solvent was removed in vacuo to give a blacksolid, 2-sulfamyl-5-acetylamino-pyridine.2-Sulfamyl-5-acetylamino-pyridine was dissolved in 0.85 N NaOH solution(500 ml), and the resulting solution was stirred at refluxingtemperature for 3.5 hours. After cooled down to room temperature, thereaction mixture was extracted with 3:1 of CHCl₃/MeOH solution (3×200ml). The aqueous layer was neutralized to pH 7, and water was removed invacuo to give the crude product, which was recrystallized from water toafford the title compound (21.6 g, 70%).

[0537] 2-Sulfamyl-5-hydrazino-pyridine hydrochloride Salt (Step 2)

[0538] To a stirred solution of 2-Sulfamyl-5-amino-pyridine (3 g) inconcentrated hydrochloric acid solution (23 ml) was added NaNO₂ (1.4 g,20 mmol) in water (23 ml) while maintaining the temperature between −5°C. and 0° C. After the reaction mixture was stirred at 0° C. for 1.5hours, SnCl₂ (19 g) in concentrated hydrochloric acid solution (25 ml)was added, and the resulting reaction mixture was stirred at 0° C. for 1hour, then room temperature overnight. The pH of the reaction solutionwas adjusted to 8 by addition of NaOH (24 g) in water (30 ml), followedby the addition of THF (200 ml). After stirred at room temperature for30 minutes, the reaction mixture was filtered through Celite®. Theaqueous layer was extracted with THF (3×200 ml) and ethyl acetate (2×200ml). The combined organic layers were dried with sodium sulfate(Na₂SO₄), and concentrated in vacuo. The product was dissolved in 10%HCl in methanol (50 ml), and the solvent was removed in vacuo to givetitle compound (2.5 g).

Preparation 5

[0539]2-(5-METHANESULFONYL-PYRIDIN-2-YL)-5-TRIFLUOROMETHYL-2H-PYRAZOL-3-OL

[0540] (5-Methanesulfonyl-pyridin-2-yl)-hydrazine (4.48 g, 20 mmol) wasmixed with methanol (20 ml), followed by the addition of trifluoroaceticacid (3.05 ml, 40 mmol), and the resulting mixture was stirred at roomtemperature for 10 minutes. 4,4,4-Trifluoro-3-oxo-butyric acid methylester (3.40 g, 20 mmol) was then added, and the reaction solution wasrefluxed for 5 hours. After cooled to room temperature, 5 N NaOHsolution (18 ml) was added, and the resultant reaction mixture washeated at 70° C. for 1.5 hours to convert all the2-(5-methanesulfonyl-pyridin-2-yl)-3-methoxy-5-trifluoromethyl-3,4-dihydro-2H-pyrazol-3-ol(2) to2-(5-methanesulfonyl-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-ol.This was then cooled down to room temperature, and diluted with ethylacetate (250 ml). The pH of the aqueous layer was adjusted to 5.5 byaddition of 5N HCl solution. The organic layer was dried with sodiumsulfate, and the solvent was removed in vacuo to give the title compound(4 g).

Preparation 6

[0541]2-FLUORO-4-(5-HYDROXY-3-TRIFLUOROMETHYL-PYRAZOL-1-YL)-BENZENESULFONAMIDE

[0542] 2-Fluoro-4-hydrazino-benzenesulfonamide hydrochloride (2.42 g)was suspended in methanol (10 ml), followed by the addition oftrifluoroacetic acid (1.53 ml), and the resultant reaction mixture wasstirred at room temperature for 10 minutes.4,4,4-trifluoro-3-oxo-butyric acid methyl ester (1.7 g) was added, andthe reaction mixture was then refluxed overnight. This was then dilutedwith EtOAc (150 ml) and saturated NaHCO₃ solution (100 ml). Afterseparation, the organic layer was dried with sodium sulfate, and thesolvent was evaporated in vacuo to give the crude product which waspurified by recrystallization from methanol (50 ml) and water (25 ml) toafford the title compound (1.2 g).

Preparation 7

[0543]2-(5-METHANESULFONYL-PYRIDIN-2-YL)-5-TRIFLUOROMETHYL-2H-PYRAZOL-3-OL

[0544] A mixture of the hydrazine (4.47 g, 20.0 mmol) and ethyltrifluoromethyl acetoacetate in dry ethanol (20 ml) was heated at reflux(90° C. bath temp.) for 4 hours. The reaction mixture was cooled to roomtemperature and 1 N NaOH (40 ml, 2 equiv) was added to the reactionmixture and stirred at room temperature for 10 minutes and at 60° C. forten minutes. The mixture was cooled to room temperature and pH adjustedto 2 with addition of 6 N aqueous HCl. Upon addition of the acid, theproduct precipitated out of the solution as a pale reddish solid whichwas collected by filtration to provide 4.89 g (80%).

Preparation 8

[0545]5-CHLORO-1-(5-METHANESULFONYL-PYRIDIN-2-YL)-3-TRIFLUOROMETHYL-1H-PYRAZOLE-4-CARBALDEHYDE

[0546] A 3-hydroxy pyrazole (1.0 g, 3.25 mmol) was suspended in dryphosphorous oxychloride (5 ml) at room temperature and dimethylformamide(DMF)(1.51 ml, 6 equivalents) was added slowly via dropwise addition.The resulting mixture was heated at 80° C. for 2.5 hours. The reactionmixture was cooled to room temperature and quenched with saturatedsodium acetate solution (5 ml) and water (5 ml). This mixture wasextracted with ether (20 ml×3). The ether layer was washed withsaturated bicarbonate (10 ml×3), and the ether layer dried (MgSO₄) andconcentrated in vacuo to provide 911 mg (79%) of the desired product asa white solid.

Preparation 9

[0547]2-(5-CHLORO-3-TRIFLUOROMETHYL-PYRAZOL-1-YL)-5-METHANESULFONYL-PYRIDINE

[0548] A 3-hydroxy pyrazole (500 mg, 1.63 mmol) was mixed withphosphorous oxychloride (5 ml) and heated to 120° C. for 48 hours. Thereaction mixture was cooled to room temperature, diluted withdichloromethane (10 ml) and washed with water (10 ml×3), dried (MgSO₄),and concentrated in vacuo to give crude white solid. This solid wasredissolved in saturated bicarbonate (40 ml) and extracted withdichloromethane (10 ml×3), dried and concentrated in vacuo to give 88 mg(17%) of pure product as a white solid.

1-26. (Cancelled).
 27. A method for treating a condition selected fromthe group consisting of arthritis, fever, common cold, dysmenorrhea,menstrual cramps, inflammatory bowel disease, Crohn's disease,emphysema, acute respiratory distress syndrome, asthma, bronchitis,chronic obstructive pulmonary disease, Alzheimer's disease, organtransplant toxicity, cachexia, allergic reactions, allergic contacthypersensitivity, cancer, tissue ulceration, peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis, recurrentgastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,synovitis, gout, ankylosing spondylitis, restenosis, periodontaldisease, epidermolysis bullosa, osteoporosis, loosening of artificialjoint implants, atherosclerosis, aortic aneurysm, periarteritis nodosa,congestive heart failure, myocardial infarction, stroke, cerebralischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerativedisorders, autoimmune disorders, Huntington's disease, Parkinson'sdisease, migraine, depression, peripheral neuropathy, pain, gingivitis,cerebral amyloid angiopathy, nootropic or cognition enhancement,amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis,corneal injury, macular degeneration, conjunctivitis, abnormal woundhealing, muscle or joint sprains or strains, tendonitis, skin disorders,myasthenia gravis, polymyositis, myositis, bursitis, bums, diabetes,tumor invasion, tumor growth, tumor metastasis, corneal scarring,scleritis, immunodeficiency diseases, sepsis, premature labor,hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet'ssyndrome, hypersensitivity, kidney disease, Rickettsial infections,Protozoan diseases, reproductive disorders, and septic shock in amammal, comprising administering to said mammal a treatment effectiveamount of a compound of the formula

wherein A is O, S, SO, SO₂ or NR⁴: X is CR⁷ or N. Y is CR⁸ or N, R¹ is(C₁-C₆)alkyl or —NH₂; R² is hydrogen, halo, hydroxy, mercapto,(C₁-C₆)alkyl, (C₂-C₆)alkenyl (C₂₋₆)alkynyl, (C₁-C₆)alkoxy optionallysubstituted with one to three halogen atoms. (C₁₋₆)alkyl-(C═O)—, formyl,formamidyl, cyano, nitro, amino, (C₁-C₆)alkylamino, [(C₁₋₆)alkyl]₂amino(C₁-C₆)alkyl-S—, —CO_H, (C₁-C₆)alkoxy-(C═O)—,(C₁-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₁-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂-N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀ aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₁-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)₄aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic. (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₁-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—, wherein said R² (C₁-C₆)alkyl group mayoptionally be substituted with one to three substituents independentlyselected from halo, hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H(C₁-Cr₆)alkoxy-(C═O)—, (C₁-C₁₀)cycloalkyl-(C═O)—O—.(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—, (—O—(C═O—,HN—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁₋₆)alkyl]₂-N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-(C₆-C₁₀)aryl-N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—; R³ is selected from the group consisting of(C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl and(C₁-C₉)heterocyclic; wherein each of said R³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl or (C₁C₉)heterocyclic groups mayoptionally be substituted with one to three substituents independentlyselected from halo, amino, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆) alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano, nitro, —OCF₃, —CF₃, (C₆-C₁₀)aryl,(C₁-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic,(C₆-C₁₀)aryloxy, (C₁-C₉)heteroaryloxy, (C₃-C₁₀)cycloalkoxy and(C₁-C₉)heterocyclic-O—; wherein each of said (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic and (C₁-C₉)heteroarylsubstituents may optionally be substituted with one to three moietiesindependently selected from halo, amino, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano, nitro, —OCF₃ and—CF₃; wherein said amino substituent or moiety may optionally besubstituted by one or two elements independently selected fromoptionally substituted (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heterocyclic and (C₁-C₉)heteroaryl, wherein said elements areoptionally substituted by halo, amino, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, —OCF₃ or —CF₃; R⁴ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl, (C₁-C₆)alkyl-(C═O)— or (C₁₋₆)alkyl-O—(C═O)—; R⁵ ishydrogen, halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—, formyl, formamidyl, cyano, nitro,—CO_H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]-N—(C═O)—, (C₆-C₁₀)aryl-HN—(C═O)—,[(C₆-C₁₀)aryl]₂-N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—,[(C₁-C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(C₁-C₆)alkoxyiminyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—,(C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-[(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—; wherein said R⁵(C₁-C₆)alkyl group may optionally be substituted with one to threesubstituents independently selected from halo, hydroxy, (C₁-C₆)alkoxy,cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O— (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—, (C₆-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂-N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N-(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂-N—(C═O)-,[(C₁-C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—, (₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— and (C₆-C₁₀)aryl-(C═O)—NH—; R⁶ ishydrogen, halo (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—, formyl, formamidyl, cyano, nitro,amino, (C₁-C₆)alkylamino. [(C₁-C₆)alkyl]₂amino; (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—(C₁-C₉)heterocyclic-(C═O)—O— (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)— (C₁-C₉)heteroaryl-O—(C═O)—.(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H?N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂-N-(C═O)—,(C₆-C₁₀)aryl-HN—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N-(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₁-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—, wherein said R⁶ (C₁-C₆)alkyl group mayoptionally be substituted with one to three substituents independentlyselected from halo, hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO_H,(C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—. (C₆-C₁₀)aryl—HN—(C═O)—,[(C₆-C₁₀)aryl]₂-N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl]-N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂-N-(C═O)—,[(C₁-C₉)heteroaryl]-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₁-C₁₀)cycloalkyloxy, (C₁-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁₋₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— and (C₆-C₁₀)aryl-(C═O)—NH—; R⁷ ishydrogen, halo, hydroxy, mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one to three halogen atoms, (C₂-C₆)alkenyl.(C₂-C₆)alkynyl, cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-(C═O)—O—, —CO_H, (C₁-₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, R₉)alkyl]₂-N—(C═O)—, nitro, amino,(C₁-C₆)alkylamino, [(C₁-C₆alkyl]₂amino, (C₁-C₆)alkyl-S—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl]₂-N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)-, (C₃-C₁₀)cycloalkyl, (C₃C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—.(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁0)aryl-(C═O)—NH—, wherein said R⁷ (C₁-C₆)alkyl group may optionally besubstituted with one to three substituents independently selected fromhalo, hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂-N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N-(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—,(C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— and (C₆-C₁₀)aryl-(C==O)—NH—; R⁸ ishydrogen, halo, hydroxy mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxy optionallysubstituted with one to three halogen atoms, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-(C═O)—O—, —CO_H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂-N—(C═O)—, nitro, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)cycloalkyl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O), (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)hetero cyclic, (C₁ C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-C═O—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—; or a pharmaceutically acceptable salt thereof.28. A method for treating a disorder or condition that can be treated byselectively inhibiting COX-2 in a mammal, comprising administering to amammal having a disorder or condition that can be treated by selectivelyinhibiting COX-2 a COX-2 selective inhibiting effective amount of acompound of the formula

wherein A is O, S, SO, SO₂ or NR⁴; X is CR⁷ or N Y is CR⁸ or N. R¹ is(C₁-C₆)alkyl or —NH₂; R is hydrogen, halo, hydroxy, mercapto,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy optionallysubstituted with one to three halogen atoms, (C₁-C₆)alkyl-(C═O)—,formyl, formamidyl, cyano, nitro, amino, (C₁-C₆)alkylamino,[(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂—N—(C═O)—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—, [(C₁-C₉)heteroaryl]₂—N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)-, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)— (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH— (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—. wherein said R² (C₁-C₆)alkyl group mayoptionally be substituted with one to three substituents independentlyselected from halo, hydroxy (C₁-C₆)alkoxy, cyano, nitro, —CO₂H,(C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₁-C₉)aryl-(C═O)—O—, (C₆-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, N₂H-(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—, (C₆-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂-N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N-(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]-N—(C═O)—,[(C₁-C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(C₆-C₁₀)aryloxy, (C₆-C₁₀)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— and(C₆-C₁₀)aryl-(C═O)—NH—; R³ is selected from the group consisting of(C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl. (C₁-C₉)heteroaryl and(C₁-C₉)heterocyclic; wherein each of said R³ (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heteroaryl or (C₁-C₉)heterocyclic groups mayoptionally be substituted with one to three substituents independentlyselected from halo, amino, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano, nitro, —OCF₃, —CF₃,(C₆-C₁₀)heteroaryl, (C₁-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl,(C₁-C₉)heterocyclic, (C₆-C₁₀)aryloxy (C₁-C₉)heteroaryloxy,(C₃-C₁₀)cycloalkoxy and (C₁-C₉)heterocyclic-O—, wherein each of said(C₆-C₁₀)aryl, (C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic and(C₁-C₉)heteroaryl substituents may optionally be substituted with one tothree moieties independently selected from halo, amino, hydroxy,(C₁-C₆)alkoxy, (₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano,nitro, —OCF₃ and —CF₁; wherein said amino substituent or moiety mayoptionally be substituted by one or two elements independently selectedfrom optionally substituted (C₁-C₆)alkyl, (C₆-C₁₀)aryl,(C₃-C₁₀)cycloalkyl, (C₁-C₉)heterocyclic and (C₁-C₆)heteroaryl, whereinsaid elements are optionally substituted by halo, amino, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, —OCF_or —CF₃; R⁴ is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl, (C₁-C₆)alkyl-(C═O)— or (C₁-C₆)alkyl-O—(C═O)—: R⁵is hydrogen, halo, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl-(C═O)—, formyl, formamidyl, cyano, nitro,—CO₂H, (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂—N—(C═O)—, (C₆-C₁₀)aryl-HN—(C═O)—, [(C₆-C_(10)aryl])₂-N-(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₉—N—(C═O)—,[(C₁-C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(C₁-C₆)alkoxyiminyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—,(C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—,(C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— or (C₆-C₁₀)aryl-(C═O)—NH—; wherein said R⁵(C₁-C₆)alkyl group may optionally be substituted with one to threesubstituents independently selected from halo, hydroxy. (C₁-C₆)alkoxy,cyano, nitro, —COIH (C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—, (C₆-C₁₀)aryl-NH—(C═O)—,[(C₆-C₁₀)aryl]₂-N—(C═O)—, (C₁-C₆)alkyl-[(C₁-C₁₀)aryl-]N-(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂—N—(C═O)—,[(C₁-C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁C₉)heterocyclic-(C═O)—NH— and (C₆-C₁₀)aryl-(C═O)—NH—; R⁶ is hydrogen,halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkynyl, (C₁-C₆)alkoxy,(C₁-C₆)alkyl-(C═O)—, formyl, formamidyl, cyano, nitro, amino,(C₁-C₆)alkylamino; [(C₁-C₆)alkyl]₂amino; (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂-N—(C═O)—,(C₆-C₁₀)aryl-HN—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₉)aryl-]N-(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—; wherein said R⁶ (C₁-C₆)alkyl group mayoptionally be substituted with one to three substituents independentlyselected from halo, hydroxyl (C₁-C₆)alkoxy, cyano, nitro, —CO₂H,(C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—, (C₆-C₁₀)aryl-HN—(C═O)—,[(C₆-C₁₀)aryl]2—N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N—(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—,[(C₁C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— and (C₆-C₁₀)aryl-(C═O)—NH—; R⁷ ishydrogen, halo, hydroxy, mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one to three halogen atoms, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-(C═O)—O—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]₂-N—(C═O)—, nitro, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₆)aryl-]N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,[(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]₂-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkoxy-(C═O)—NH—,(C₁-C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—; wherein said R⁷ (C₁-C₆)alkyl group mayoptionally be substituted with one to three substituents independentlyselected from halo, hydroxy, (C₁-C₆)alkoxy, cyano, nitro, —CO₂H,(C₁-C₆)alkoxy-(C═O)—, (C₃-C₁₀)cycloalkyl-(C═O)—O—,(C₁-C₉)heteroaryl-(C═O)—O—, (C₁-C₉)heterocyclic-(C═O)—O—,(C₆-C₁₀)aryl-(C═O)—O—, (C₃-C₁₀)cycloalkyl-O—(C═O)—,(C₁-C₉)heteroaryl-O—(C═O)—, (C₁-C₉)heterocyclic-O—(C═O)—,(C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—, (C₁-C₆)alkyl-HN—(C═O)—,[(C₁-C₆)alkyl]₂-N—(C═O)—, (C₆-C₁₀)aryl-HN—(C═O)—,[(C₆-C₁₀)aryl]₂-N—(C═O)—, (C₁-C₆)alkyl-[(C₆-C₁₀)aryl-]N-(C═O)—,(C₃-C₁₀)cycloalkyl-NH—(C═O)—, (C₁-C₉)heteroaryl-NH—(C═O)—,(C₁-C₉)heterocyclic-NH—(C═O)—, [(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—,[(C₁-C₉)heteroaryl]₂-N—(C═O)—, [(C₁-C₉)heterocyclic]₂-N—(C═O)—,(₆-C₁₀)aryl, (C₆-C₁₀)aryloxy, (C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkyloxy, (C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl,(C₁-C₉)heteroaryloxy, (C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic,(C₁-C₉)heterocyclic-O—, (C₁-C₉)heterocyclic-(C═O)—,(C₁-C₆)alkoxy-(C═O)—NH—, (C₁-C₆)alkyl-(C═O)—NH—,(C₃-C₁₀)cycloalkyl-(C═O)—NH—, (C₁-C₉)heteroaryl-(C═O)—NH—,(C₁-C₉)heterocyclic-(C═O)—NH— and (C₆-C₁₀)aryl-(C═O)—NH—, R⁸ ishydrogen, halo, hydroxy, mercapto, (C₁-C₆)alkyl, (C₁-C₆)alkoxyoptionally substituted with one to three halogen atoms, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, cyano, formyl, formamidyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-(C═O)—O—, —CO₂H, (C₁-C₆)alkoxy-(C═O)—,(C₃-C₁₀)cycloalkyl-(C═O)—O—, (C₁-C₉)heteroaryl-(C═O)—O—,(C₁-C₉)heterocyclic-(C═O)—O—, (C₆-C₁₀)aryl-(C═O)—O—,(C₃-C₁₀)cycloalkyl-O—(C═O)—, (C₁-C₉)heteroaryl-O—(C═O)—,(C₁-C₉)heterocyclic-O—(C═O)—, (C₆-C₁₀)aryl-O—(C═O)—, H₂N—(C═O)—,(C₁-C₆)alkyl-HN—(C═O)—, [(C₁-C₆)alkyl]-N—(C═O)—, nitro, amino,(C₁-C₆)alkyl amino, [(C₁-C₆)alkyl]₂amino, (C₁-C₆)alkyl-S—,(C₆-C₁₀)aryl-NH—(C═O)—, [(C₆-C₁₀)aryl]₂-N—(C═O)—,(C₁-C₆)alkyl-[(C₆-C₁₀)aryl-N—(C═O)—, (C₃-C₁₀)cycloalkyl-NH—(C═O)—,(C₁-C₉)heteroaryl-NH—(C═O)—, (C₁-C₉)heterocyclic-NH—(C═O)—,(C₃-C₁₀)cycloalkyl]₂-N—(C═O)—, [(C₁-C₉)heteroaryl]-N—(C═O)—,[(C₁-C₉)heterocyclic]₂-N—(C═O)—, (C₆-C₁₀)aryl, (C₆-C₁₀)aryloxy,(C₆-C₁₀)aryl-(C═O)—, (C₃-C₁₀)cycloalkyl, (C₃C₁₀)cycloalkyloxy,(C₃-C₁₀)cycloalkyl-(C═O)—, (C₁-C₉)heteroaryl, (C₁-C₉)heteroaryloxy,(C₁-C₉)heteroaryl-(C═O)—, (C₁-C₉)heterocyclic, (C₁-C₉)heterocyclic-O—,(C₁-C₉)heterocyclic-(C═O)—, (C₁-C₆)alkocy-(C═O)—NH—,(C₁C₆)alkyl-(C═O)—NH—, (C₃-C₁₀)cycloalkyl-(C═O)—NH—,(C₁-C₉)heteroaryl-(C═O)—NH—, (C₁-C₉)heterocyclic-(C═O)—NH— or(C₆-C₁₀)aryl-(C═O)—NH—, or a pharmaceutically acceptable salt thereof.